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Recent Articles in BMC Cancer

Wilcox CB, Feddes GO, Willet-Brozick JE, Hsu LC, Deloia JA, Baysal BE
Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer.
BMC Cancer. 2007 Dec 11;7(1):223.
ABSTRACT: BACKGROUND: Ovarian cancer (OvCa) most often derives from ovarian surface epithelial (OSE) cells. Several lines of evidence strongly suggest that increased exposure to progesterone (P4) protects women against developing OvCa. However, the underlying mechanisms of this protection are incompletely understood. METHODS: To determine downstream gene targets of P4, we established short term in vitro cultures of non-neoplastic OSE cells from six subjects, exposed the cells to P4 (10-6 M) for five days and performed transcriptional profiling with oligonucleotide microarrays containing over 22,000 transcripts. RESULTS: We identified concordant but modest gene expression changes in cholesterol/lipid homeostasis genes in three of six samples (responders), whereas the other three samples (non-responders) showed no expressional response to P4. The most up-regulated gene was TMEM97 which encodes a transmembrane protein of unknown function (MAC30). Analyses of outlier transcripts, whose expression levels changed most significantly upon P4 exposure, uncovered coordinate up-regulation of 14 cholesterol biosynthesis enzymes, insulin-induced gene 1, low density lipoprotein receptor, ABCG1, endothelial lipase, stearoyl- CoA and fatty acid desaturases, long-chain fatty-acyl elongase, and down-regulation of steroidogenic acute regulatory protein and ABCC6. Highly correlated tissue-specific expression patterns of TMEM97 and the cholesterol biosynthesis genes were confirmed by analysis of the GNF Atlas 2 universal gene expression database. Real-time quantitative RT-PCR analyses revealed 2.4-fold suppression of the TMEM97 gene expression in short-term cultures of OvCa relative to the normal OSE cells. CONCLUSIONS: These findings suggest that a co-regulated transcript network of cholesterol/lipid homeostasis genes and TMEM97 are downstream targets of P4 in normal OSE cells and that TMEM97 plays a role in cholesterol and lipid metabolism. The P4-induced alterations in cholesterol and lipid metabolism in OSE cells might play a role in conferring protection against OvCa. [Abstract/Link to Full Text]

Elkum N, Dermime S, Ajarim D, Al-Zahrani A, Alsayed A, Tulbah A, Al Malik O, Alshabanah M, Ezzat A, Al-Twegieri T
Being 40 or younger is an independent risk factor for relapse in operable breast cancer patients: The Saudi Arabia experience.
BMC Cancer. 2007 Dec 5;7(1):222.
ABSTRACT: BACKGROUND: Breast cancer in young Saudi's women is a crucial problem. According to the 2002 annual report of Saudi National Cancer Registry, breast cancers that developed before the age of 40 comprise 26.4% of all female breast cancers comparing to 6.5% in the USA. Breast cancer in young patients is often associated with a poorer prognosis, but there has been a scarcity of published data in the Middle East population. METHODS: Total of 876 breast cancer patients seen at King Faisal Specialist Hospital & Research Centre (KFSH&RC) between 1986 and 2002 were reviewed. Patients were divided in two age groups: [less than or equal to] 40 years and above 40 years. The clinicopathological characteristics and treatment outcomes were compared between younger and older age groups. RESULTS: Median age at presentation was 45 years. A total of 288 (33.2%) patients were less than or equal to 40 years. Hormone receptors were positive in 69% of patients less than or equal to 40 and 78.2% of patients above 40 (p = 0.009). There was a significantly higher incidence of grade III tumor in younger patients compared to older patients (p = 0.0006). Stage, tumor size, lymphatic/vascular invasion, number of nodes and axillary lymph node status, did not differ significantly between the two age groups. Younger patients had a greater probability of recurrence at all time periods (p=0.035). Young age had a negative impact on survival of patients with positive axillary lymph nodes (p = 0.030) but not on survival of patients with negative lymph nodes (p = 0.695). Stage, tumor size, nodal status and hormonal receptors had negative impact on survival. Adjuvant chemotherapy was administered to 87.9% of younger and 65.6% of older patients (p < 0.0001). In terms of hormone therapy, the proportion of tamoxifen treated patients was significantly lower in young age group (p < 0.0001). No significant difference in radiation therapy between the two groups. CONCLUSION: Young age is an independent risk factor for relapse in operable Saudi breast cancer patients. The fundamental biology of young age breast cancer patients needs to be elucidated, and development of tailored treatment for this patient population is crucial. [Abstract/Link to Full Text]

Hayslip J, Chaudhary U, Green M, Meyer M, Dunder S, Sherman C, Salzer S, Kraft A, Montero AJ
Bortezomib in combination with celecoxib in patients with advanced solid tumors: a phase I trial.
BMC Cancer. 2007 Dec 3;7(1):221.
ABSTRACT: BACKGROUND: COX-2 inhibitors, such as celecoxib, and ubiquitin-proteasome pathway inhibitors, such as bortezomib, can down-regulate NF-kappaB, a transcription factor implicated in tumor growth. The objective of this study was to determine the maximum tolerated dose and dose-limiting toxicities of bortezomib in combination with celecoxib in patients with advanced solid tumors. METHODS: Patients received escalating doses of bortezomib either on a weekly schedule (days 1, 8, 15, 22, and 29 repeated every 42 days) or on a twice-weekly administration schedule (days 1, 4, 8, and 11 repeated every 21 days), in combination with escalating doses of celecoxib twice daily throughout the study period from 200 mg to 400 mg twice daily. RESULTS: No dose-limiting toxicity was observed during the study period. Two patients had stable disease lasting for four and five months each, and sixteen patients developed progressive disease. CONCLUSIONS: The combination of bortezomib and celecoxib was well tolerated, without dose limiting toxicities observed throughout the dosing ranges tested, and will be studied further at the highest dose levels investigated. Trial registration number NCT00290680. [Abstract/Link to Full Text]

Mazieres J, Tovar D, He B, Acosta-Jacobo N, Marty-Detraves C, Clanet C, Pradines A, Jablons DM, Favre G
Epigenetic regulation of RhoB loss of expression in lung cancer.
BMC Cancer. 2007 Nov 30;7(1):220.
ABSTRACT: BACKGROUND: RhoB is down-regulated in most lung cancer cell lines and tumor tissues when compared with their normal counterparts. The mechanism of this loss of expression is not yet deciphered. METHODS: Since no mutation has been reported in the RhoB sequence, we investigated the epigenetic regulation of RhoB expression by analyzing the effect of HDAC inhibitors and methyltransferase inhibitors, by direct sequencing after bisulfite treatment and by methylation specific PCR. RESULTS: We first showed that histone deacetylase (HDAC) inhibitors induce a significant RhoB re-expression in lung cancer cell lines whereas only a slight effect was observed with methyl transferase inhibitors. As promoter methylation is the most common epigenetic process in lung cancer, we performed methylation specific PCR and sequence analysis after bisulfite treatment and demonstrated that RhoB was methylated neither in lung cancer cell lines nor in tumor tissues. We also showed that a variable number of tandem repeats sequences in the 5' region of the RhoB gene was involved in HDAC response. CONCLUSION: We thus propose that RhoB regulation of expression occurs mainly by histone deacetylation rather than by promoter hypermethylation and that this process can be modulated by specific 5' sequences within the promoter. [Abstract/Link to Full Text]

Saban MR, Towner R, Smith N, Abbott A, Neeman M, Davis CA, Simpson C, Maier J, Memet S, Wu XR, Saban R
Lymphatic vessel density and function in experimental bladder cancer.
BMC Cancer. 2007 Nov 29;7(1):219.
ABSTRACT: The lymphatics form a second circulatory system that drains the extracellular fluid and proteins from the tumor microenvironment, and provides an exclusive environment in which immune cells interact and respond to foreign antigen. Both cancer and inflammation are known to induce lymphangiogenesis. However, little is known about bladder lymphatic vessels and their involvement in cancer formation and progression. METHODS: A double transgenic mouse model was generated by crossing a bladder cancer-induced transgenic, in which SV40 large T antigen was under the control of uroplakin II promoter, with another transgenic mouse harboring a lacZ reporter gene under the control of an NF-kB-responsive promoter (kB-lacZ) exhibiting constitutive activity of b-galactosidase in lymphatic endothelial cells. In this new mouse model (SV40-lacZ), we examined the lymphatic vessel density (LVD) and function (LVF) during bladder cancer progression. LVD was performed in bladder whole mounts and cross-sections by fluorescent immunohistochemistry (IHC) using LYVE-1 antibody. LVF was assessed by real-time in vivo imaging techniques using a contrast agent (biotin-BSA-Gd-DTPA-Cy5.5; Gd-Cy5.5) suitable for both magnetic resonance imaging (MRI) and near infrared fluorescence (NIRF). In addition, IHC of Cy5.5 was used for time-course analysis of co-localization of Gd-Cy5.5 with LYVE-1-positive lymphatics and CD31-positive blood vessels. RESULTS: SV40-lacZ mice develop bladder cancer and permitted visualization of lymphatics. A significant increase in LVD was found concomitantly with bladder cancer progression. Double labeling of the bladder cross-sections with LYVE-1 and Ki-67 antibodies indicated cancer-induced lymphangiogenesis. MRI detected mouse bladder cancer, as early as 4 months, and permitted to follow tumor sizes during cancer progression. Using Gd-Cy5.5 as a contrast agent for MRI-guided lymphangiography, we determined a possible reduction of lymphatic flow within the tumoral area. In addition, NIRF studies of Gd-Cy5.5 confirmed its temporal distribution between CD31-positive blood vessels and LYVE-1 positive lymphatic vessels. CONCLUSIONS: SV40-lacZ mice permit the visualization of lymphatics during bladder cancer progression. Gd-Cy5.5, as a double contrast agent for NIRF and MRI, permits to quantify delivery, transport rates, and volumes of macromolecular fluid flow through the interstitial-lymphatic continuum. Our results open the path for the study of lymphatic activity in vivo and in real time, and support the role of lymphangiogenesis during bladder cancer progression. [Abstract/Link to Full Text]

Genelhu MC, Cardoso SV, Gobbi H, Cassali GD
A comparative study between mixed-type tumours from human salivary and canine mammary glands.
BMC Cancer. 2007 Nov 28;7(1):218.
ABSTRACT: BACKGROUND: In comparative pathology, the canine mammary tumours have special interest because their similarities with the human breast cancer. The mixed tumours are uncommon lesions in the human breast, but they are the found most frequently in the mammary gland of the female dogs and in the human salivary glands. The aim of the study was to compare clinical, morphological and immunohistochemical features of human salivary and canine mammary gland mixed tumours, in order to evaluate the latter as an experimental model for salivary gland tumours. METHODS: Ten examples of each mixed tumour type (human pleomorphic adenoma and carcinomas ex-pleomorphic adenomas and canine mixed tumour and metaplastic carcinoma) were evaluated. First, clinical and morphologic aspects of benign and malignant variants were compared between the species. Then, streptavidin-biotin-peroxidase immunohistochemistry was performed to detect the expression of cytokeratins, vimentin, p63 protein, estrogen receptor, beta-catenin, and E-cadherin. RESULTS: After standardization, similar age and site distributions were observed in human and canine tumours. Histological similarities were identified in the comparison of the benign lesions as well. Metaplastic carcinomas also resembled general aspects of carcinomas ex-pleomorphic adenomas in morphological evaluation. Additionally, immunohistochemical staining further presented similar antigenic expression between lesions. CONCLUSIONS: There are many similar features between human salivary and canine mammary gland mixed tumours. This observation is of great relevance for those interested in the study and management of salivary gland tumours, since canine lesions may constitute useful comparative models for their investigations. [Abstract/Link to Full Text]

Motokura T, Nakamura Y, Sato H
Aberrant overexpression of an epithelial marker, 14-3-3sigma, in a subset of hematological malignancies.
BMC Cancer. 2007 Nov 25;7(1):217.
ABSTRACT: BACKGROUND: 14-3-3sigma is a p53-mediated cell-cycle inhibitor in epithelial cells. The expression of 14-3-3sigma is frequently altered in cancers of epithelial origin associated with altered DNA methylation. Since its involvement in a non-epithelial tumor is unknown, we examined 14-3-3sigma expression in patients with haematological malignancies. METHODS: We analyzed 41 hematopoietic cell lines and 129 patients with a variety of hematological malignancies for 14-3-3sigma expression with real-time RT-PCR. We also examined protein levels by Western blot analysis and DNA methylation status of the 14-3-3sigma gene by methylation-specific PCR analysis of bisulfite-treated DNA. In addition, mutations of p53 gene were identified by RT-PCR-SSCP analysis and the expression levels of 14-3-3sigma were compared with those of other cell-cycle inhibitor genes, CDKN2A and ARF. RESULTS: The expression levels of 14-3-3sigma mRNA in almost all cell lines were low and comparable to those in normal hematopoietic cells except for 2 B-cell lines. On the contrary, 14-3-3sigma mRNA was aberrantly overexpressed frequently in mature lymphoid malignancies (30 of 93, 32.3%) and rarely in acute leukemia (3 of 35, 8.6%). 14-3-3sigma protein was readily detectable and roughly reflected the mRNA level. In contrast to epithelial tumors, methylation status of the 14-3-3sigma gene was not associated with expression in hematological malignancies. Mutations of p53 were identified in 12 patients and associated with lower expression of 14-3-3sigma. The expression levels of 14-3-3sigma, CDKN2A and ARF were not correlated with but rather reciprocal to one another, suggesting that simultaneous overexpression of any two of them is incompatible with tumor growth. CONCLUSIONS: 14-3-3sigma, an epithelial cell marker, was overexpressed significantly in a subset of mature lymphoid malignancies. This is the first report of aberrant 14-3-3sigma expression in non-epithelial tumors in vivo. Since the significance of 14-3-3sigma overexpression is unknown even in epithelial tumors such as pancreatic cancers, further analysis of regulation and function of the 14-3-3sigma gene in non-epithelial as well as epithelial tumors is warranted. [Abstract/Link to Full Text]

Yang YC, Ho TC, Chen SL, Lai HY, Wu JY, Tsao YP
Inhibition of cell motility by troglitazone in human ovarian carcinoma cell line.
BMC Cancer. 2007 Nov 20;7(1):216.
ABSTRACT: BACKGROUND: Troglitazone (TGZ) is a potential anticancer agent. Little is known about the effect of this agent on cancer cell migration. METHODS: Human ovarian carcinoma cell line, ES-2 cells were treated with various concentrations of TGZ. Cell migration was evaluated by wound-healing and Boyden chamber transwell experiments. PPAR gamma expression was blocked by PPAR gamma small interfering RNA. The effects of TGZ on phosphorylation of FAK, PTEN, Akt were assessed by immunoblotting using phospho-specific antibodies. The cellular distribution of paxillin, vinculin, stress fiber and PTEN was assessed by immunocytochemistry. RESULTS: TGZ dose- and time-dependently impaired cell migration through a PPAR gamma independent manner. TGZ treatment impaired cell spreading, stress fiber formation, tyrosine phosphorylation of focal adhesion kinase (FAK), and focal adhesion assembly in cells grown on fibronectin substratum. TGZ also dose- and time-dependently suppressed FAK autophosphorylation and phosphorylation of the C-terminal of PTEN (a phosphatase). At concentration higher than 10 micromolar, TGZ caused accumulation of PTEN in plasma membrane, a sign of PTEN activation. CONCLUSION: These results indicate that TGZ can suppress cultured ES-2 cells migration. Our data suggest that the anti-migration potential of TGZ involves in regulations of FAK and PTEN activity. [Abstract/Link to Full Text]

Sheahan S, Bellamy CO, Dunbar DR, Harrison DJ, Prost S
Deficiency of G1 regulators P53, P21Cip1 and/or pRB decreases hepatocyte sensitivity to TGFbeta cell cycle arrest.
BMC Cancer. 2007 Nov 19;7(1):215.
ABSTRACT: BACKGROUND: TGFbeta is critical to control hepatocyte proliferation by inducing G1-growth arrest through multiple pathways leading to inhibition of E2F transcription activity. The retinoblastoma protein pRB is a key controller of E2F activity and G1/S transition which can be inhibited in viral hepatitis. It is not known whether the impairment of pRb would alter the growth inhibitory potential of TGFbeta in disease. We asked how Rb-deficiency would affect responses to TGFbeta-induced cell cycle arrest. RESULTS: Primary hepatocytes isolated from Rb-floxed mice were infected with an adenovirus expressing CRE-recombinase to delete the Rb gene. In control cells treatment with TGFbeta prevented cells to enter S phase via decreased cMYC activity, activation of P16 and P21 and reduction of E2F activity. In Rb-null hepatocytes, cMYC activity decreased slightly but P16 was not activated and the great majority of cells continued cycling. Rb is therefore central to TGFbeta-induced cell cycle arrest in hepatocytes. However some Rb-null hepatocytes remained sensitive to TGFbeta-induced cell cycle arrest. As these hepatocytes expressed very high levels of P21 and P53 we investigated whether these proteins regulate pRB-independent signaling to cell cycle arrest by evaluating the consequences of disruption of p53 and p21Cip1. Hepatocytes deficient in p53 or p21Cip1 showed diminished growth inhibition by TGFbeta. Double deficiency had a similar impact showing that in cells containing functional pRB; P21 and P53 work through the same pathway to regulate G1/S in response to TGFbeta. In Rb-deficient cells however, p53 but not p21 deficiency had an additive effect highlighting a pRB-independent-P53-dependent effector pathway of inhibition of E2F activity. CONCLUSION: The present results show that otherwise genetically normal hepatocytes with disabled p53, p21Cip1 or Rb genes respond less well to the antiproliferative effects of TGFbeta. As the function of these critical cellular proteins can be impaired by common causes of chronic liver disease and HCC, including viral hepatitis B and C proteins, we suggest that disruption of pRB function, and to a lesser extend P21Cip1 and P53 in hepatocytes may represent an additional new mechanism of escape from TGFbeta-growth-inhibition in the inflammatory milieu of chronic liver disease and contribute to cancer development. [Abstract/Link to Full Text]

Stucker I, Loriot M, N'koutchou G, Cenee S, Bodin L, Mulot C, Gelu-Simeon M, Pelletier L, Broniwicki J, Degos F, Beaune P, Laurent-Puig P, Hemon D, Trinchet J, Pelletier G
UDP-glucuronosyltransferase UGT1A7 genetic polymorphisms in hepatocellular carcinoma: a differential impact according to seropositivity of HBV or HCV markers?
BMC Cancer. 2007 Nov 19;7(1):214.
ABSTRACT: BACKGROUND: We conducted a case-control study to evaluate the role of UDP-glucuronosyltransferase 1A7 (UGT1A7) polymorphisms in the onset of hepatocellular carcinoma (HCC). Patients and Methods The study included 165 patients with HCC, 134 with cirrhosis and 142 controls without liver disease, matched for age and hospital. All were men younger than 75 years. HCC and cirrhosis patients were stratified according to time since cirrhosis diagnosis. RESULTS: We found a positive association between the UGT1A7*3/*3 genotype and HCC when the comparison was restricted to patients whose disease was of viral origin [OR=3.4 (0.3-45)] but a negative association when it included only alcoholic patients [OR=0.1 (0.02-0.6)]. CONCLUSION: Our study shows that UGT1A7 may play a role in hepatocellular carcinogenesis and that this role may differ according to the primary cause of the cirrhosis. [Abstract/Link to Full Text]

Staab A, Loeffler J, Said HM, Diehlmann D, Katzer A, Beyer M, Fleischer M, Schwab F, Baier K, Einsele H, Flentje M, Vordermark D
Effects of HIF-1 inhibition by chetomin on hypoxia-related transcription and radiosensitivity in HT 1080 human fibrosarcoma cells.
BMC Cancer. 2007 Nov 13;7(1):213.
ABSTRACT: BACKGROUND: Hypoxia-inducible factor-1 (HIF-1) overexpression has been linked to tumor progression and poor prognosis. We investigated whether targeting of HIF-1 using chetomin, a disrupter of the interaction of HIF-1 with the transcriptional coactivator p300, influences the radiosensitivity of hypoxic HT 1080 human fibrosarcoma cells. METHODS: Optimal dose of chetomin was determined by EGFP-HRE gene reporter assay in stably transfected HT 1080 cells. Cells were assayed for expression of the hypoxia-inducible genes carbonic anhydrase 9 (CA9) and vascular endothelial growth factor (VEGF) by RT-PCR and for clonogenic survival after irradiation with 2, 5 or 10 Gy, under normoxic or hypoxic (0.1% O2, 12 h) conditions in the presence or absence of chetomin (150 nM, 12 h, pre-treatment of 4 h). RESULTS: Chetomin treatment significantly reduced CA9 and VEGF mRNA expression in hypoxic cells to 44.4+/- 7.2% and 39.6+/-16.0%, respectively, of untreated hypoxic controls. Chetomin clearly reduced the modified oxygen enhancement ratio (OER') compared to untreated cells, from 2.02 to 1.27, from 1.86 to 1.22 and from 1.49 to 1.06 at the 50%, 37% and 10% clonogenic survival levels, respectively. CONCLUSIONS: HIF-1 inhibition by chetomin effectively reduces hypoxia-dependent transcription and radiosensitizes hypoxic HT 1080 human fibrosarcoma cells in vitro. [Abstract/Link to Full Text]

Lentini L, Amato A, Schillaci T, Di Leonardo A
Simultaneous Aurora-A/STK15 overexpression and centrosome amplification induce chromosomal instability in tumour cells with a MIN phenotype.
BMC Cancer. 2007 Nov 13;7(1):212.
ABSTRACT: BACKGROUND: Genetic instability is a hallmark of tumours and preneoplastic lesions. The predominant form of genome instability in human cancer is chromosome instability (CIN). CIN is characterized by chromosomal aberrations, gains or losses of whole chromosomes (aneuploidy), and it is often associated with centrosome amplification. Centrosomes control cell division by forming a bipolar mitotic spindle and play an essential role in the maintenance of chromosomal stability. However, whether centrosome amplification could directly cause aneuploidy is not fully established. Also, alterations in genes required for mitotic progression could be involved in CIN. A major candidate is represented by Aurora-A/STK15 that associates with centrosomes and is overexpressed in several types of human tumour. METHODS: Centrosome amplification were induced by hydroxyurea treatment and visualized by immunofluorescence microscopy. Aurora-A/STK15 ectopic expression was achieved by retroviral infection and puromycin selection in HCT116 tumour cells. Effects of Aurora-A/STK15 depletion on centrosome status and ploidy were determined by Aurora-A/STK15 transcriptional silencing by RNA interference. Changes in the expression levels of some mitotic genes were determined by Real time RT-PCR. RESULTS: We investigated whether amplification of centrosomes and overexpression of Aurora-A/STK15 induce CIN using as a model system a colon carcinoma cell line (HCT116). We found that in HCT116 cells, chromosomally stable and near diploid cells harbouring a MIN phenotype, centrosome amplification induced by hydroxyurea treatment is neither maintained nor induces aneuploidy. On the contrary, ectopic overexpression of Aurora-A/STK15 induced supernumerary centrosomes and aneuploidy. Aurora-A/STK15 transcriptional silencing by RNA interference in cells ectopically overexpressing this kinase promptly decreased cell numbers with supernumerary centrosomes and aneuploidy. CONCLUSIONS: Our results show that centrosome amplification alone is not sufficient to induce chromosomal instability in colon cancer cells with a MIN phenotype. Alternatively, centrosome amplification has to be associated with alterations in genes regulating mitosis progression such as Aurora-A/STK15 to trigger CIN. [Abstract/Link to Full Text]

Yang S, Du J, Wang Z, Yuan W, Qiao Y, Zhang M, Zhang J, Gao S, Yin J, Sun B, Zhu T
BMP-6 promotes E-cadherin expression through repressing deltaEF1 in breast cancer cells.
BMC Cancer. 2007 Nov 13;7(1):211.
ABSTRACT: BACKGROUND: Bone morphogenetic protein-6 (BMP-6) is critically involved in many developmental processes. Recent studies indicate that BMP-6 is closely related to tumor differentiation and metastasis. METHODS: Quantitative RT-PCR was used to determine the expression of BMP-6, E-cadherin, and deltaEF1 at the mRNA level in MCF-7 and MDA-MB-231 breast cancer cells, as well as in 16 breast cancer specimens. Immunoblot analysis was used to measure the expression of deltaEF1 at the protein level in deltaEF1-overexpressing and deltaEF1-interfered MDA-MB-231 cells. Luciferase assay was used to determine the rhBMP-6 or deltaEF1 driven transcriptional activity of the E-cadherin promoter in MDA-MB-231 cells. Quantitative CHIP assay was used to detect the direct association of deltaEF1 with the E-cadherin proximal promoter in MDA-MB-231 cells. RESULTS: MCF-7 breast cancer cells, an ER+ cell line that expressed high levels of BMP-6 and E-cadherin exhibited very low levels of deltaEF1 transcript. In contrast, MDA-MB-231 cells, an ER- cell line had significantly reduced BMP-6 and E-cadherin mRNA levels, suggesting an inverse correlation between BMP-6/E-cadherin and deltaEF1. To determine if the same relationship exists in human tumors, we examined tissue samples of breast cancer from human subjects. In 16 breast cancer specimens, the inverse correlation between BMP-6/E-cadherin and deltaEF1 was observed in both ER+ cases (4 of 8 cases) and ER- cases (7 of 8 cases). Further, we found that BMP-6 inhibited deltaEF1 transcription, resulting in an up-regulation of E-cadherin mRNA expression. This is consistent with our analysis of the E-cadherin promoter demonstrating that BMP-6 was a potent transcriptional activator. Interestingly, ectopic expression of deltaEF1 was able to block BMP-6-induced transactivation of E-cadherin, whereas RNA interference-mediated down-regulation of endogenous deltaEF1 in breast cancer cells abolished E-cadherin transactivation by BMP-6. In addition to down-regulating the expression of deltaEF1, BMP-6 also physically dislodged deltaEF1 from E-cadherin promoter to allow the activation of E-cadherin transcription. CONCLUSION: We conclude that repression of deltaEF1 plays a key role in mediating BMP-6-induced transcriptional activation of E-cadherin in breast cancer cells. Consistent with the fact that higher level of deltaEF1 expression is associated with more invasive phenotype of breast cancer cells, our collective data suggests that deltaEF1 is likely the switch through which BMP-6 restores E-cadherin-mediated cell-to-cell adhesion and prevents breast cancer metastasis. [Abstract/Link to Full Text]

Oldervoll LM, Loge JH, Kaasa S, Lydersen S, Hjermstad MJ, Thorsen L, Holte H
Physical activity in Hodgkin's lymphoma survivors with and without chronic fatigue compared with the general population - a cross-sectional study.
BMC Cancer. 2007 Nov 12;7(1):210.
ABSTRACT: BACKGROUND: Hodgkin's lymphoma survivors (HLSs) commonly report chronic fatigue, defined as high levels of fatigue for 6 months or more. Underlying mechanisms are poorly understood. Based upon knowledge from other populations, lifestyle parameters may be related to this increased and persistent fatigue. The primary objective of the present study was to assess self-reported levels of physical activity, smoking habits and sleep patterns in HLSs with and without chronic fatigue. The secondary objective was to compare these results with data from age and gender adjusted data from the general population (Gen-Pop). METHODS: The Fatigue Questionnaire (FQ) and questions about daily smoking, sleep patterns and level of physical activity were completed by 476 HLSs treated at Rikshospitalet-Radiumhospitalet Trust (RR). The Gen-Pop data was derived from 56.999 inhabitants in a Norwegian county responding to a mail survey. Fischer's exact test, chi square test and t-tests were used to compare groups. P-values < .05 were considered statistically significant. A logistic regression analysis was performed in comparing the Gen-Pop with the HLSs. RESULTS: Level of physical activity, smoking habits and sleep patterns did not differ significantly between HLSs with and without chronic fatigue. The multivariate logistic regression analysis adjusting for different covariates, showed significantly more physically active men among HLSs compared with the Gen-Pop (OR = 1.50, CI 1.04 - 2.17), p = .031. No significant difference was found among females (OR = 1.20, CI = 0.83 - 1.74), p = .33. CONCLUSIONS: Lifestyle parameters did not seem to be related to increased and persistent fatigue among HLSs. The results may indicate that the experience of Hodgkin's lymphoma increases the level of physical activity among male HLSs. [Abstract/Link to Full Text]

Klein-Scory S, Zapatka M, Eilert-Micus C, Hoppe S, Schwarz E, Schmiegel W, Hahn SA, Schwarte-Waldhoff I
High-level inducible Smad4-reexpression in the cervical cancer cell line C4-II is associated with a gene expression profile that predicts a preferential role of Smad4 in extracellular matrix composition.
BMC Cancer. 2007 Nov 12;7(1):209.
ABSTRACT: BACKGROUND: Smad4 is a tumor suppressor frequently inactivated in pancreatic and colorectal cancers. We have recently reported loss of Smad4 in every fourth carcinoma of the uterine cervix. Smad4 transmits signals from the TGF-beta superfamily of cytokines and functions as a versatile transcriptional co-modulator. The prevailing view suggests that Smad4s tumor suppressor function primarily resides in its capability to mediate TGF-beta growth inhibitory responses. However, accumulating evidence indicates, that the acquisition of TGF-beta resistance and loss of Smad4 may be independent events in the carcinogenic process. Through inducible reexpression of Smad4 in cervical cancer cells we wished to shed more light on this issue and to identify target genes implicated in Smad4 dependent tumor suppression. METHODS: Smad4-deficient human C4-II cervical carcinoma cells were used to establish inducible Smad4 reexpression using the commercial Tet-on system (Clontech). The impact of Smad4 reexpression on cell growth was analysed in vitro and in vivo. Transcriptional responses were assessed through profiling on cDNA macroarrays (Clontech) and validated through Northern blotting. RESULTS: Clones were obtained that express Smad4 at widely varying levels from approximately physiological to 50fold overexpression. Smad4 mediated tumor suppression in vivo was observed at physiological expression levels as well as in Smad4 overexpressing clones. Smad4 reexpression in a dose-dependent manner was associated with transcriptional induction of extracellular matrix associated genes BigH3, fibronectin and PAI-1 in response to TGF-beta. Smad4-dependent regulation of these secreted Smad4 targets is not restricted to cervical carcinoma cells and was confirmed in pancreatic carcinoma cells reexpressing Smad4 after retroviral transduction and in a stable Smad4 knockdown model. Cell-cycle associated classical TGF-beta target genes c-myc, p21 and p15, on the other hand, remained unaltered. CONCLUSION: Our results show that Smad4-mediated tumor suppression in cervical cancer cells is not due to restoration of TGF-beta growth inhibitory responses. Rather, tumor cell ECM interactions may be more relevant for Smad4-mediated tumor suppression. C4-II cells with high level inducible Smad4 expression may serve as a model to indicate further Smad4 targets responsive to diverse environmental stimuli operative in vivo. [Abstract/Link to Full Text]

Bu X, Jia F, Wang W, Guo X, Wu M, Wei L
Coupled down-regulation of mTOR and telomerase activity during fluorouracil-induced apoptosis of hepatocarcinoma Cells.
BMC Cancer. 2007 Nov 12;7(1):208.
ABSTRACT: BACKGROUND: Hepatocellular carcinoma (HCC) is the most invasive and frequently diagnosed malignancy and the second leading cause of cancer death in many regions of Asia. The PI3K/Akt/mTOR signal pathway is involved in multiple cellular functions including proliferation, differentiation, tumorigenesis, and apoptosis. Up-regulation of telomerase activity is thought to be a critical step leading to cell transformation. METHODS: This study investigated changes in mTOR pathway and telomerase activity in hepatocarcinoma cell line SMMC-7721 treated with chemotherapeutic agent 5-fluorouracil (5-Fu). We detected apoptosis of hepatocarcinoma cells by TUNEL assay. Telomerase activity, hTERT transcription level and p- p70 S6k was demonstrated by the telomeric repeat amplification protocol and silver staining assay, Dual-Luciferase Reporter Assay and Western blot analysis respectively . RESULTS: Treating SMMC-7721 cells with 5-Fu leads to apoptosis of the cells, and reduction in telomerase activity, as well as a dramatic reduction in the activated form of p70 S6 kinase, a mTOR substrate. The 5-Fu treatment nearly abolishes transcription of hTERT (the major component of telomerase) mRNA. Treating SMMC-7721 cells with Rapamycin, a specific mTOR inhibitor, significantly reduce hTERT protein level but did not affect hTERT transcription. 5-Fu and rapamycin were synergistic in regards to down-regulation of telomerase activity in hepatocarcinoma cells. CONCLUSIONS: These results suggest that chemotherapeutic agent 5-Fu may down-regulate telomerase activity at both transcriptional level and PI3K/Akt/mTOR pathway-dependent post-transcriptional level to facilitate hepatocellular carcinoma cell apoptosis. [Abstract/Link to Full Text]

Marfe G, Di Stefano C, Silvestri R, Abruzzese E, Catalano G, Di Renzo L, Filomeni G, Giorda E, La Regina G, Morgante E, Ciriolo MR, Russo MA, Amadori S, Sinibaldi-Salimei P
Pyrrolo[1,2-B][1,2,5]Benzothiadiazepines (PBTDs) induces apoptosis in K562 cells.
BMC Cancer. 2007 Nov 9;7(1):207.
ABSTRACT: BACKGROUND: The objective of this study was aimed at gaining insights into the molecular mechanism induced cell death (apoptosis) by PYRROLO[1,2-b][1,2,5]BENZOTHIADIAZEPINES (PBTDs) series compounds, using human (K562) cells as a model. METHODS: We focused our attention on some members of the PBTDs family to test their potential apoptotic activity in K562 cells. Important apoptotic activity was demonstrated as evidenced with the concentration and the percentage of the cell death quantified by measuring PI-uptake by flow cytometry, DNA fragmentation, and analyzed by agarose gel electrophoresis generating a characteristic ladder pattern of discontinuous DNA fragments. The expression of Bcl-2 family was tested using western blotting and transfection method. RESULTS: PBTDs-mediated suppression of K562 cell proliferation was induced by apoptosis characterized by the appearance of DNA fragmentation and was associated with the poly(ADP-ribose)polymerase (PARP) cleavage. PBTD-1 and -3 treatment resulted in caspase-3 activation through down-regulation of Bcl-2 and up-regulation of Bax. Furthermore, we used K562/vector and K562/bcl-2 cells, which were generated by transfection of the cDNA of the Bcl-2 gene. As compared with K562/vector, K562/Bcl-2 cells exhibited a 4-fold greater expression of Bcl-2. Treatment with 10 uM PBTD-1 and -3 for 24 h produced morphological features of apoptosis and DNA fragmentation in K562/vector cells, respectively. In contrast, PBTD-1 and -3-induced caspase-3 activation and apoptosis were inhibited in K562/Bcl-2. Furthermore, Bcl-2 overexpressig cells exhibited less cytocromr c relese during PBTDs-induced apoptosis. CONCLUSIONS: These results indicate that PBTDs effectively induces the apoptosis of K562 leukemia cells through the activation of caspase cascades. In addition, this findings indicate that Bcl-2 inhibits PBTD-1 and -3 induced-apoptosis by mechanism that interferes with cytocrome c release and activity of caspase-3 that is involved in the execution of apoptosis. [Abstract/Link to Full Text]

Boccia S, Sayed-Tabatabaei FA, Persiani R, Gianfagna F, Rausei S, Arzani D, La Greca A, D'Ugo D, La Torre G, van Duijn CM, Ricciardi G
Polymorphisms in metabolic genes, their combination and interaction with tobacco smoke and alcohol consumption and risk of gastric cancer: a case-control study in an Italian population.
BMC Cancer. 2007 Nov 8;7(1):206.
ABSTRACT: BACKGROUND: The distribution and the potential gene-gene and gene-environment interaction of selected metabolic genetic polymorphisms was investigated in relation to gastric cancer risk in an Italian population. METHODS: One hundred and seven cases and 254 hospital controls, matched by age and gender, were genotyped for CYP1A1, CYP2E1, mEH, GSTM1, GSTT1, NAT2 and SULT1A1 polymorphisms. Haplotype analysis was performed for EPHX1 exons 3 and 4, as well as CYP2E1 RsaI (*5B allele) and CYP2E1 DraI (*6 allele) polymorphisms. The effect modification by alcohol and cigarette smoking was tested with the heterogeneity test, while the attributable proportion (AP) was used to measure the biological interaction from the gene-gene interaction analysis. RESULTS: Gastric cancer risk was found to be associated with the inheritance of GSTT1 null genotype (OR= 2.10, 95%CI: 1.27-3.44) and the SULT1A1 His/His genotype (OR= 2.46, 95%CI: 1.03-5.90). No differences were observed for the haplotype distributions among cases and controls. For the first time an increased risk was detected among individuals carrying the *6 variant allele of CYP2E1 if ever-drinkers (OR = 3.70; 95%CI: 1.45-9.37) with respect to never-drinkers (OR = 0.18; 95% CI: 0.22-1.46) (p value of heterogeneity among the two estimates = 0.001). Similarly, the effect of SULT1A1 variant genotype resulted restricted to ever-smokers, with an OR of 2.58 (95%CI: 1.27-5.25) for the carriers of His allele among smokers, and an OR of 0.86 (95%CI: 0.45-1.64) among never-smokers (p value of heterogeneity among the two estimates = 0.03). The gene-gene interaction analyses demonstrated that individuals with combined GSTT1 null and NAT2 slow acetylators had an additional increased risk of gastric cancer, with an OR of 3.00 (95%CI: 1.52-5.93) and an AP of 52%. CONCLUSION: GSTT1, SULT1A1 and NAT2 polymorphisms appear to modulate individual's susceptibility to gastric cancer in this Italian population, particularly when more than one unfavourable genotype is present, or when combined with cigarette smoke. The increased risk for the carriers of CYP2E1*6 variant allele among drinkers need to be confirmed by larger prospective studies. [Abstract/Link to Full Text]

Petersson S, Bylander A, Yhr M, Enerback C
S100A7 (Psoriasin), highly expressed in Ductal Carcinoma In Situ (DCIS), is regulated by IFN-gamma in mammary epithelial cells.
BMC Cancer. 2007 Nov 6;7(1):205.
ABSTRACT: BACKGROUND: The aim of the present work was to explore signal transduction pathways used in the regulation of S100A7 (psoriasin). Members of the S100 gene family participate in many important cellular functions. Psoriasin, S100A8 (calgranulin A) and S100A9 (calgranulin B) are expressed in ductal carcinoma in situ (DCIS), as well as in the hyperproliferative skin disease, psoriasis. In the latter condition, a disturbance in the STAT pathway has recently been reported. This pathway is implicated in the regulation of IFN-gamma, widely recognized as a key cytokine in psoriasis. IFN-gamma also exerts anti-tumor action in a number of tumor cell types, including breast cancer. We therefore examined the effect of IFN-gamma and STAT-signaling on the psoriasin expression. METHODS: We established a TAC2 mouse mammary epithelial cell line with tetracycline-inducible psoriasin expression (Tet-Off). Viability in cell culture was estimated using MTS assay. Protein and gene expression were evaluated by Western blotting and quantitative real-time PCR. Statistical analyses were assessed using a one-tailed, paired t-test. RESULTS: We report the downregulation of psoriasin by IFN-gamma in the MDA-MB-468 breast cancer cell line, as well as the downregulation of psoriasin induced by anoikis in cell lines derived from different epithelial tissues. In contrast, IFN-gamma had no suppressive effect on calgranulin A or calgranulin B. IFN-gamma is an important activator of the STAT1 pathway and we confirmed an active signaling pathway in the cell lines that responded to IFN-gamma treatment. In contrast, in the SUM190 breast carcinoma cell line, IFN-gamma did not suppress the expression of endogenous psoriasin. Moreover, a reduced phosphorylation of the STAT1 protein was observed. We showed that IFN-gamma treatment and the inhibition of the transcription factor NFkappaB had a synergistic effect on psoriasin levels. Finally, in TAC2 cells with tetracycline-induced psoriasin expression, we observed the increased viability of psoriasin-expressing cells after IFN-gamma treatment. CONCLUSION: Our data support the possibility that psoriasin expression is transcriptionally suppressed by IFN-gamma and that this effect is likely to be mediated by the activation of the STAT1 signaling pathway. The increased viability of psoriasin-expressing cells after IFN-gamma exposure suggests that psoriasin expression leads to the development of an apoptosis-resistant phenotype. [Abstract/Link to Full Text]

Saban MR, Hellmich HL, Simpson C, Davis CA, Lang ML, Ihnat MA, O'Donnell MA, Wu XR, Saban R
Repeated BCG treatment of mouse bladder selectively stimulates small GTPases and HLA antigens and inhibits single-spanning uroplakins.
BMC Cancer. 2007 Nov 2;7(1):204.
ABSTRACT: Background Despite being a mainstay for treating superficial bladder carcinoma and a promising agent for interstitial cystitis, the precise mechanism of Bacillus Calmette-Guerin (BCG) remains poorly understood. It is particularly unclear whether BCG is capable of altering gene expression beyond its well-recognized pro-inflammatory effects and how this relates to its therapeutic efficacy. The objective of this study was to determine differentially expressed genes in the mouse bladder following repeated intravesical BCG therapy. Methods Mice were transurethrally instilled with BCG or pyrogen-free on days 1, 7, 14, and 21. Seven days after the last instillation, urothelia along with the submucosa was removed and amplified ds-DNA was prepared from control- and BCG-treated bladder mucosa and used to generate suppression subtractive hybridization (SSH). Plasmids from control- and BCG-specific differentially expressed clones and confirmed by Virtual Northern were then purified and the inserts were sequenced and annotated. Finally, chromatin immune precipitation combined with real-time polymerase chain reaction assay (ChIP/Q-PCR) was used to validate SSH-selected transcripts. Results Repeated intravesical BCG treatment induced an up regulation of genes associated with antigen presentation (B2M, HLA-A, HLA-DQA1, HLA-DQB2, HLA-E, HLA-G, IGHG, and IGH) and representatives of two IFN-induced small GTPase families: the GBPs (GBP1, GBP2, and GBP5) and the p47GTPases (IIGTP1, IIGTP2, and TGTP). Genes expressed in saline-treated bladders but down-regulated by BCG included: the single-spanning uroplakins (UPK3a and UPK2), SPRR2G, GSTM5, and RSP 19. Conclusion Here we introduced a hypothesis-generator approach to determine key genes involved in the urothelium/sumbmucosa responses to BCG therapy. Urinary bladder responds to repeated BCG treatment by up-regulating not only antigen presentation-related genes, but also GBPs and p47 small GTPases, both potentially serving to mount a resistance to the replication of the Mycobacterium. It will be of tremendous future interest to determine whether these immune response cascades play a role in the anti-cancer effects exerted by BCG. [Abstract/Link to Full Text]

Keam B, Im SA, Kim HJ, Oh DY, Kim JH, Lee SH, Chie EK, Han W, Kim DW, Moon WK, Kim TY, Park IA, Noh DY, Heo DS, Ha SW, Bang YJ
Prognostic impact of clinicopathologic parameters in stage II/III breast cancer treated with neoadjuvant docetaxel and doxorubicin chemotherapy: paradoxical features of the triple negative breast cancer.
BMC Cancer. 2007 Nov 1;7(1):203.
ABSTRACT: BACKGROUND: Prognostic factors in locally advanced breast cancer treated with neoadjuvant chemotherapy differ from those of early breast cancer. The purpose of this study was to identify the clinical significance of potential predictive and prognostic factors in breast cancer patients treated by neoadjuvant chemotherapy. METHODS: A total of 145 stage II and III breast cancer patients received neoadjuvant docetaxel/doxorubicin chemotherapy were enrolled in this prospective study. We examined the clinical and biological factors (ER, PR, p53, c-erbB2, bcl-2, and Ki-67) by immunohistochemistry. We analyzed clinical outcome and their correlation with clinicopathologic parameters. RESULTS: Among the clinicopathologic parameters investigated, none of the marker was correlated with response rate (RR) except triple negative phenotype. Patients with triple negative phenotype showed higher RR (83.0% in triple negative vs. 62.2% in non-triple negative, p=0.012) and pathologic complete RR (17.0% in triple negative vs. 3.1% in non-triple negative, p=0.005). However, relapse free survival (RFS) and overall survival (OS) were significantly shorter in triple negative breast cancer patients (p<0.001, p=0.021, respectively). Low histologic grade, positive hormone receptors, positive bcl-2 and low level of Ki-67 were associated with prolonged RFS. In addition, positive ER and positive bcl-2 were associated with prolonged OS. In our homogeneous patient population, initial clinical stage reflects RFS and OS more precisely than pathologic stage. In multivariate analysis, initial clinical stage was the only significant independent prognostic factor to impact on OS (hazard ratio 3.597, p=0.044). CONCLUSION: Several molecular markers provided useful predictive and prognostic information in stage II and III breast cancer patients treated with neoadjuvant docetaxel/doxorubicin chemotherapy. Triple negative phenotype was associated with shorter survival, even though it was associated with a higher response rate to neoadjuvant chemotherapy. [Abstract/Link to Full Text]

Assimakopoulou M, Kondyli M, Gatzounis G, Maraziotis T, Varakis J
Neurotrophin receptors expression and JNK pathway activation in human astrocytomas.
BMC Cancer. 2007 Oct 31;7(1):202.
ABSTRACT: BACKGROUND: Neurotrophins are growth factors that regulate cell growth, differentiation and apoptosis in the nervous system. Their diverse actions are mediated through two different transmembrane - receptor signaling systems: Trk receptor tyrosine kinases (TrkA, TrkB, TrkC) and p75NTR neurotrophin receptor. Trk receptors promote cell survival and differentiation while p75NTR induces, in most cases, the activity of JNK-p53-Bax apoptosis pathway or suppresses intracellular survival signaling cascades. Robust Trk activation blocks p75NTR -induced apoptosis by suppressing the JNK-p53-Bax pathway. The aim of this exploratory study was to investigate the expression levels of neurotrophin receptors, Trks and p75NTR, and the activation of JNK pathway in human astrocytomas and in adjacent non-neoplastic brain tissue. METHODS: Formalin-fixed paraffin-embedded serial sections from 33 supratentorial astrocytomas (5 diffuse fibrillary astrocytomas, WHO grade II; 6 anaplastic astrocytomas, WHO grade III; 22 glioblastomas multiforme, WHO grade IV) were immunostained following microwave pretreatment. Polyclonal antibodies against TrkA, TrkB, TrkC and monoclonal antibodies against p75NTR and phosphorylated forms of JNK (pJNK) and c-Jun (pc-Jun) were used. The labeling index (LI), defined as the percentage of positive (labeled) cells out of the total number of tumor cells counted, was determined. RESULTS: Moderate to strong, granular cytoplasmic immunoreactivity for TrkA, TrkB and TrkC receptors was detected in greater than or equal to 10% of tumor cells in the majority of tumors independently of grade; on the contrary, p75NTR receptor expression was found in a small percentage of tumor cells (~1%) in some tumors. The endothelium of tumor capillaries showed conspicuous immunoreactivity for TrkB receptor. Trk immunoreactivity seemed to be localized in some neurons and astrocytes in non-neoplastic tissue. Phosphorylated forms of JNK (pJNK) and c-Jun (pc-Jun) were significantly co-expressed in a tumor grade-dependent manner (p<0.05). Interestingly, a statistically significant (p<0.05) reverse relationship between Trk receptors LIs and pc-Jun/pJNK LIs was noted in some glioblastomas multiforme. CONCLUSIONS: In the context of astrocytomas, Trk receptors (TrkA, TrkB, TrkC) expression may promote tumor growth independently of grade. Furthermore, activation of JNK pathway may contribute to progression towards malignancy. Considering the fact that regional tumor heterogeneity may be a limiting factor for immunohistochemical studies, the significance of the reverse relationship between Trk receptors and pc-Jun/pJNK LIs with respect to biological behavior of human astrocytomas requires further evaluation. [Abstract/Link to Full Text]

Gomez S, Tan S, Keegan TH, Clarke CA
Disparities in mammographic screening for Asian women in California: a cross-sectional analysis to identify meaningful groups for targeted intervention.
BMC Cancer. 2007 Oct 26;7(1):201.
ABSTRACT: BACKGROUND: Breast cancer is the most commonly diagnosed cancer among the rapidly growing population of Asian Americans; it is also the most common cause of cancer mortality among Filipinas. Asian women continue to have lower rates of mammographic screening than women of most other racial/ethnic groups. While prior studies have described the effects of sociodemographic and other characteristics of women on non-adherence to screening guidelines, they have not identified the distinct segments of the population who remain at highest risk of not being screened. METHODS: To better describe characteristics of Asian women associated with not having a mammogram in the last two years, we applied recursive partitioning to population-based data (N=1521) from the 2001 California Health Interview Survey (CHIS), for seven racial/ethnic groups of interest: Chinese, Japanese, Filipino, Korean, South Asian, Vietnamese, and all Asians combined. RESULTS: We identified two major subgroups of Asian women who reported not having a mammogram in the past two years and therefore, did not follow mammography screening recommendations: 1) women who have never had a pap exam to screen for cervical cancer (68% had no mammogram), and 2) women who have had a pap exam, but have no women's health issues (osteoporosis, using menopausal hormone therapies, and/or hysterectomy) nor a usual source of care (62% had no mammogram). Only 19% of Asian women who have had pap screening and have women's health issues did not have a mammogram in the past two years. In virtually all ethnic subgroups, having had pap or colorectal screening were the strongest delineators of mammography usage. Other characteristics of women least likely to have had a mammogram included: Chinese non-U.S. citizens or citizens without usual source of health care, Filipinas with no health insurance, Koreans without women's health issues and public or no health insurance, South Asians less than age 50 who were unemployed or non-citizens, and Vietnamese women who were never married. CONCLUSIONS: We identified distinct subgroups of Asian women at highest risk of not adhering to mammography screening guidelines; these data can inform outreach efforts aimed at reducing the disparity in mammography screening among Asian women. [Abstract/Link to Full Text]

Liu C, Lu P, Lu Y, Xu H, Wang S, Chen J
Clinical implications of metastatic lymph node ratio in gastric cancer.
BMC Cancer. 2007 Oct 24;7(1):200.
ABSTRACT: BACKGROUND: The 5-year survival rate in patients with gastric cancer is still poor, and lymph node metastasis is considered one of the most important prognostic factors. However, there are controversies in the classification of lymph node metastasis in gastric cancer. This study was carried out to investigate whether the metastatic lymph node ratio is a reliable classification of lymph node metastasis in gastric cancer in Chinese. METHODS: 224 cases with gastric cancer with more than D1 dissection were retrospectively reviewed. The association between the total number of resected lymph nodes and the number of metastatic lymph nodes was determined. The prognostic value of the metastastic node ratio, defined as the ratio of the number of metastatic lymph nodes over the total number of resected lymph nodes, and the pN classification was assessed. RESULTS: The number of metastatic lymph node increased with the number of total resected lymph nodes. A Cox regression revealed that the metastatic node ratio, the number of metastatic nodes, histological type, and histological growth pattern independently influenced prognosis. The 5-year survival rates were 78%, 61%, 25%, 0% in cases with a metastastic node ratio of 0%, >0% but <40%, 40-80%, >80%, respectively (P<0.001), and were 78%, 62%, 38%, 0% in cases with gastric cancer histologically classified as pN0, pN1, pN2, pN3, respectively (P<0.001). CONCLUSION: The metastatic lymph node ratio is a simple and useful independent prognostic factor. It may obviate possible confounding factors that are related to stage migration, and should be considered as an important component in the lymph node category. [Abstract/Link to Full Text]

Choi JE, Park SH, Kim KM, Lee WK, Kam S, Cha SI, Kim CH, Kang YM, Kim YC, Han SB, Jung TH, Park JY
Polymorphisms in the epidermal growth factor receptor gene and the risk of primary lung cancer: a case-control study.
BMC Cancer. 2007;7199.
BACKGROUND: Polymorphisms in Epidermal Growth Factor Receptor (EGFR) gene may influence EGFR production and/or activity, thereby modulating susceptibility to lung cancer. To test this hypothesis, we investigated the association between polymorphisms in the EGFR gene and the risk of lung cancer in a Korean population. METHODS: We first examined the frequencies of 39 candidate polymorphisms in the EGFR gene in 27 healthy Korean individuals. After then, we genotyped five polymorphisms (127378C>T, 142285G>A, 162093G>A, 181946C>T and 187114T>C) that have variant allele frequencies greater than 10%, in 582 lung cancer patients and in 582 healthy controls. RESULTS: Of the 5 polymorphisms, the 181946C>T genotype distribution was significantly different between the cases and controls (P = 0.04). Compared with the 181946 CC + CT genotype, the 181946 TT genotype was associated with a significantly decreased risk of lung cancer (adjusted OR = 0.63, 95% CI = 0.45-0.88, P = 0.007). When the analyses were stratified by smoking status, the protective effect of the TT genotype was statistically significant in ever-smokers (adjusted OR = 0.59, 95% CI = 0.41-0.86, P = 0.007), but not in never-smokers (adjusted OR = 0.89, 95% CI = 0.45-1.75, P = 0.73; P = 0.08, test for homogeneity). Consistent with the results of the genotyping analysis, the CGGCT haplotype with the 181946C allele was associated with a significantly increased risk of lung cancer compared to the CGGTT haplotype carrying the 181946T allele (adjusted OR = 1.50, 95% CI = 1.09-2.07, P = 0.012 and Bonferroni corrected P-value = 0.048). CONCLUSION: These results suggest that the EGFR polymorphisms, particularly the 181945C>T polymorphism, could be used as markers for the genetic susceptibility to lung cancer. [Abstract/Link to Full Text]

Grunewald TG, Kammerer U, Kapp M, Eck M, Dietl J, Butt E, Honig A
Nuclear localization and and cytosolic overexpression of LASP-1 correlates with tumor size and nodal-positivity of human breast carcinoma.
BMC Cancer. 2007 Oct 23;7(1):198.
ABSTRACT: BACKGROUND: LIM and SH3 protein 1 (LASP-1), initially identified from human breast cancer, is a specific focal adhesion protein involved in cell proliferation and migration, which was reported to be overexpressed in 8-12 % of human breast cancers and thought to be exclusively located in cytoplasm. METHODS: In the present work we analyzed the cellular and histological expression pattern of LASP-1 and its involvement in biological behavior of human breast cancer through correlation with standard clinicopathological parameters and expression of c-erbB2 (HER-2/neu), estrogen- (ER) and progesterone-receptors (PR). For this purpose immunohistochemical staining intensity and percentage of stained cells were semi-quantitatively rated to define a LASP-1 immunoreactive score (LASP-1-IRS). LASP-1-IRS was determined in 83 cases of invasive ductal breast carcinomas, 25 ductal carcinomas in situ (DCIS) and 18 fibroadenomas. Cellular LASP-1 distribution and expression pattern was visualized by immunofluorescence and confocal microscopy and assessed through separate Western blots of nuclear and cytosolic preparations of BT-20, MCF-7, MDA-MB231, and ZR-75/1 breast cancer cells. RESULTS: Statistical analysis revealed that the resulting LASP-1-IRS was significantly higher in invasive carcinomas compared to fibroadenomas (p = 0.0176). Strong cytoplasmatic expression of LASP-1 was detected in 55.4 % of the invasive carcinomas, which correlated significantly with nuclear LASP-1-positivity (p = 0.0014), increased tumor size (p = 0.0159) and rate of nodal-positivity (p = 0.0066). However, levels of LASP-1 expression did not correlate with average age at time point of diagnosis, histological tumor grading, c-erbB2-, ER- or PR-expression. Increased nuclear localization and cytosolic expression of LASP-1 was found in breast cancer with higher tumor stage as well as in rapidly proliferating epidermal basal cells. Confocal microscopy and separate Western blots of cytosolic and nuclear preparations confirmed nuclear localization of LASP-1. CONCLUSIONS: The current data provide evidence that LASP-1 is not exclusively a cytosolic protein, but is also detectable within the nucleus. Increased expression of LASP-1 in vivo is present in breast carcinomas with higher tumor stage and therefore may be related with worse prognosis concerning patients' overall survival. [Abstract/Link to Full Text]

Brunsvig PF, Andersen A, Aamdal S, Kristensen V, Olsen H
Pharmacokinetic analysis of two different docetaxel dose levels in patients with non-small cell lung cancer treated with docetaxel as monotherapy or with concurrent radiotherapy.
BMC Cancer. 2007 Oct 23;7(1):197.
ABSTRACT: BACKGROUND: Previous pharmacokinetic studies with docetaxel have mostly used 3-weekly (75 mg/m2 and 100 mg/m2) or weekly regimens (35-40 mg/m2).The pharmacokinetics and radiosensitizing efficacy of weekly 20 mg/m2 docetaxel, has however not been well characterized. We examined the pharmacokinetics of weekly docetaxel when administered with concurrent radiotherapy and compared the results with a 3-weekly 100 mg/m2 regimen. METHODS: Thirty-four patients with non small cell lung cancer (NSCLC) were included in this study, 19 receiving 100 mg/m2 docetaxel 3-weekly as single therapy, and 15 receiving 20 mg/m2 docetaxel weekly with concurrent radiotherapy. A newly developed HPLC method was used for measuring docetaxel levels, capable of quantifying docetaxel in plasma down to the nanomolar level. RESULTS: The HPLC method showed detectable concentrations of docetaxel in plasma even after 72 hours. In the present study we have demonstrated that median docetaxel plasma levels of 3 nM can be obtained 72 hours after a dose of 20 mg/m2. CONCLUSION: The pharmacokinetics of docetaxel is characterized by great inter-individual variability and at some time points plasma concentrations for 20 mg/m2 and 100 mg/m2 docetaxel were overlapping. Extrapolation of these results indicates that radio sensitizing docetaxel concentrations may be present for as long as 1 week, thus supporting the use of 20 mg /m2 weekly docetaxel. [Abstract/Link to Full Text]

Arabzadeh A, Troy TC, Turksen K
Changes in the distribution pattern of Claudin tight junction proteins during the progression of mouse skin tumorigenesis.
BMC Cancer. 2007 Oct 18;7(1):196.
ABSTRACT: BACKGROUND: Despite the fact that morphological and physiological observations suggest that the tight junction (TJ)-based permeability barrier is modified/disrupted in tumorigenesis, the role of members of the Claudin (Cldn) family of TJ proteins is not well-understood. Using a well-established two-stage chemical carcinogenesis model, we investigated the temporal and spatial changes in expression of those Cldns that we have previously demonstrated to be important in epidermal differentiation and the formation of the epidermal permeability barrier, i.e., Cldn1, Cldn6, Cldn11, Cldn12 and Cldn18. METHODS: The lower dorsal backskin of mice was treated topically with 7,12-dimethylbenz(a)anthracene (DMBA) and following a 10-day incubation period, 12-O-tetradecanoyl-phorbol-13-acetate (TPA) was applied three times a week to the same area. Backskin samples were dissected 2, 4, 6, 8 and 12 weeks after the initiation of the experimental protocol and immunohistochemistry was performed on sections using antibodies against the following: Cldn1, Cldn6, Cldn11, Cldn12, Cldn18, Ki67 and CD3. RESULTS: Our data indicate that along with the changes in epidermal cell morphology and differentiation that occur during tumor formation, there is a dramatic change in Cldn distribution consistent with cell polarity and barrier selectivity changes. Specifically, in the early stages of DMBA/TPA treatment, the suprabasal-specific Cldns occupy an expanded zone of expression corresponding to an increased number of suprabasal epidermal cell layers. As tumorigenesis progressed, the number of suprabasal epidermal layers positive for Cldn6, Cldn11, Cldn12 and Cldn18 was reduced, especially in the lower strata of the expanded suprabasal zone. In addition, a variably reduced cell membrane association of those differentiation-specific Cldns was observed, especially within the infiltrating epidermal structures. In contrast, Cldn1 (which is normally expressed in all the living layers of the epidermis) remained restricted to the cell membrane throughout the tumorigenesis protocol. However commencing 2 weeks after treatment there was a marked decrease in the number of Cldn1-positive basal cells, and the zone of Cldn1-null epidermal cells was expanded up into the lower stratified epidermis throughout the progression of DMBA/TPA treatment. In addition, there was no Cldn1 localization in the infiltrating epidermal structures of the tumorigenic epidermis. CONCLUSIONS: This is the first demonstration of the changes in Cldn expression in the progression of DMBA/TPA-induced skin tumors; however further investigation into the molecular mechanisms regulating the observed changes in barrier selectivity during tumorigenesis is required. [Abstract/Link to Full Text]

Karlsson A, Nordigarden A, Jonsson JI, Soderkvist P
Bcl11b mutations identified in murine lymphomas increase the proliferation rate of hematopoietic progenitor cells.
BMC Cancer. 2007 Oct 17;7(1):195.
ABSTRACT: BACKGROUND: The telomeric region of mouse chromosome 12 has previously shown frequent allelic loss in murine lymphoma. The Bcl11b gene has been identified and suggested as a candidate tumor suppressor gene within this region. In this study, we aimed to elucidate whether Bcl11b is mutated in lymphomas with allelic loss, and whether the mutations we detected conferred any effect on cell proliferation and apoptosis. METHODS: Mouse lymphomas induced by 1,3-butadiene or 2',3'-dideoxycytidine were analysed for mutations in the Bcl11b gene using single strand conformation analysis and direct DNA sequencing. Effects on cell proliferation by the detected mutations were studied by expressing wild-type and mutant Bcl11b in the cytokine-dependent hematopoietic progenitor cell line FDC-P1, lacking endogenous Bcl11b expression. RESULTS: Missense and frameshift (FS) mutations were identified in 7 of 47 tumors (15%). Interestingly, all mutations were found between amino acids 778-844 which encode the three C-terminal DNA-binding zinc fingers. In FDC-P1 cells, wild-type Bcl11b suppressed cell proliferation, whereas the mutated versions (S778N, K828T, Y844C and FS823) enhanced proliferation several-fold. CONCLUSIONS: The genetic alterations detected in this study suggest that the three C-terminal zinc fingers of Bcl11b are important for the DNA-binding. Cell proliferation was suppressed by overexpression of wild-type Bcl11b but enhanced by mutant Bcl11b, indicating that these mutations may be an important contributing factor to lymphomagenesis in a subset of tumors. [Abstract/Link to Full Text]

He JF, Jia WH, Fan Q, Zhou XX, Qin HD, Shugart YY, Zeng YX
Genetic polymorphisms of TLR3 are associated with Nasopharyngeal carcinoma risk in Cantonese population.
BMC Cancer. 2007;7194.
BACKGROUND: Nasopharyngeal carcinoma is endemic in Southern China, displays a strong relationship with genetic susceptibility and associates with Epstein-Barr virus infection. Toll-like receptor 3 (TLR3) plays an important role in the antivirus response. Therefore, we examined the association between TLR3 gene polymorphisms and NPC susceptibility. METHODS: We performed a case-control study of 434 NPC cases and 512 healthy controls matched on age, sex and residence. Both cases and controls are of Cantonese origin from Southern China. Genetic variants in TLR3 were determined by polymerase chain reaction (PCR)-based DNA direct sequencing and four SNPs were genotyped in all samples. RESULTS: Our results showed that allele C for SNP 829A/C increased NPC risk significantly ((p = 0.0068, OR = 1.49, 95%CI:1.10-2.00). When adjusted for age, gender and VCA-IgA antibody titers, the NPC risk was reduced significantly among individuals who carried the haplotype "ATCT" compared to those who carried the most common haplotype "ACCT" (p = 0.0054, OR = 0.028; 95% CI (0.002-0.341). CONCLUSION: The TLR3 polymorphisms may be relevant to NPC susceptibility in the Cantonese population, although the reduction in NPC risk is modest and the biological mechanism of the observed association merits further investigation. [Abstract/Link to Full Text]