BRCA1-mediated signaling pathways in ovarian carcinogenesis.
ABSTRACT The link between loss or defect in functional BRCA1 and predisposition for development of ovarian and breast cancer is well established. Germ-line mutations in BRCA1 are responsible for both hereditary breast and ovarian cancer, which is around 5-10% for all breast and 10-15% of all ovarian cancer cases. However, majority of cases of ovarian cancer are sporadic in nature. The inactivation of cellular BRCA1 due to mutations or loss of heterozygosity is one of the most commonly observed events in such cases. Complement-resistant retroviral BRCA1 vector, MFG-BRCA1, is the only approved gene therapy for ovarian cancer patients by the Federal and Drug Administration. Given the limited available information, there is a need to evaluate the effects of BRCA1 on the global gene expression pattern for better understanding the etiology of the disease. Here, we use Ingenuity Pathway Knowledge Base to examine the differential pattern of global gene expression due to stable expression of BRCA1 in the ovarian cancer cell line, SKOV3. The functional analysis detected at least five major pathways that were significantly (p < 0.05) altered. These include: cell to cell signaling and interaction, cellular function and maintenance, cellular growth and proliferation, cell cycle and DNA replication, and recombination repair. In addition, we were able to detect several biologically relevant genes that are central for various signaling networks involved in cellular homeostasis; TGF-β1, TP53, c-MYC, NF-κB and TNF-α. This report provides a comprehensive rationale for tumor suppressor function(s) of BRCA1 in ovarian carcinogenesis.
- [Show abstract] [Hide abstract]
ABSTRACT: Objective To analyze effects of high mobility group AT-hook 2 (HMGA2) on malignant degree, invasion, metastasis, proliferation and cellular morphology of ovarian cancer cells. Methods Three methods were applied to observe the effect on HMGA2 expression in ovarian cancer cells and ovarian epithelial cells. Results After the application of siRNA-HMGA2, number of T29A2-cell clones was decreased, there was significant difference compared with the negative control Block-iT. After application of let-7c, number of T29A2+ cell clones was decreased significantly, however, after the application of Anti-let-7, the number of clones restored, and there was no significant difference compared with the negative control group. After interference, the number of T29A2- cells which passed through Matrigel polycarbonate membrane were significantly lower than the negative control group. After the treatment of siRNA-HMGA2, let-7c and sh-HMGA2 respectively, growth and proliferation of T29A2-, T29A2+ and SKOV3 were slower, and the phenomenon was most obvious in SKOV3. Stable interference of HMGA2 induced mesenchymal-epithelial changes in the morphology of SKOV3-sh-HMGA2. Conclusions HMGA2 can promote malignant transformation of ovarian cancer cells, enhance cell invasion and metastasis, and promote cell growth and proliferation of ovarian cancer cells, which can cause ovarian cancer to progress rapidly and affect the quality of life.Asian Pacific Journal of Tropical Medicine 04/2014; 7(4):289–292. · 0.93 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Molecular classification of breast cancer is based, in part, on the presence or absence of amplification of the human epidermal growth factor receptor 2 (ERBB2) gene, which leads to HER2 protein overproduction. While the presence of the overexpressed HER2 protein is a necessary precondition for sensitivity to anti-HER2 therapies, many patients develop resistance. Thus, identification of the downstream effectors of this pathway will help in understanding mechanism(s) of chemoresistance and further, the identified molecules themselves may have the potential to be used as therapeutic targets. In this work, we studied the proteomic changes that accompany the HER2 gene amplification to identify potential new therapeutic targets and biomarkers. We analyzed bio-triplicate proteome samples extracted from wild-type MCF-7 human breast cancer cells and their isogenic stably overexpressing HER2 (amplified) transfectants. In total, 2455 unique proteins were quantified with 1278 of them differentially expressed in HER2 normal and HER2 overexpressing MCF-7 cells. Select biomarker candidates of particular interest were validated by western blotting, and evaluated for clinical relevance by immunohistochemical assessment of protein abundance in breast tumor biopsies. HER2 transfection produced marked changes in proteins related to multiple aspects of cancer biology, and the identified expression patterns were recapitulated in the clinical samples. Biological Significances Breast cancer is a major cause of death in women. Molecular classification of breast cancer is based, in part, on the presence or absence of amplification of the human epidermal growth factor receptor 2 (ERBB2) gene, which leads to HER2 protein overproduction that triggers intracellular signaling events that drive proliferation, invasion, metastases, and resistance to apoptosis. While the presence of the overexpressed HER2 gene product, HER2 protein, is a necessary precondition for sensitivity to the therapeutic monoclonal antibody trastuzumab, the downstream effects of HER2 protein overexpression are incompletely understood. In this work, we applied quantitative proteomics to identify proteomic changes accompanying ERBB2 gene amplification. The significances of this work include 1) identification of new biomarkers associated with the HER2 phenotype, 2) measurement of the magnitude of the proteomic changes triggered by amplification of this single gene, and 3) better understanding of the downstream biological changes triggered by HER2 overexpression.Journal of proteomics 07/2013; · 5.07 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Aberrant Wnt signalling is implicated in numerous human cancers, and understanding the effects of modulation of pathway members may lead to the development of novel therapeutics. Expression of secreted frizzled related protein 4 (SFRP4), an extracellular modulator of the Wnt signalling pathway, is progressively lost in more aggressive ovarian cancer phenotypes. Here we show that recombinant SFRP4 (rSFRP4) treatment of a serous ovarian cancer cell line results in inhibition of β-catenin dependent Wnt signalling as measured by TOP/FOP Wnt reporter assay and decreased transcription of Wnt target genes, Axin2, CyclinD1 and Myc. In addition, rSFRP4 treatment significantly increased the ability of ovarian cancer cells to adhere to collagen and fibronectin, and decreased their ability to migrate across an inflicted wound. We conclude that these changes in cell behaviour may be mediated via mesenchymal to epithelial transition (MET), as rSFRP4 treatment also resulted in increased expression of the epithelial marker E-cadherin, and reduced expression of Vimentin and Twist. Combined, these results indicate that modulation of a single upstream gatekeeper of Wnt signalling can have effects on downstream Wnt signalling and ovarian cancer cell behaviour, as mediated through epithelial to mesenchymal plasticity (EMP). This raises the possibility that SFRP4 may be used both diagnostically and therapeutically in epithelial ovarian cancer.PLoS ONE 01/2013; 8(1):e54362. · 3.53 Impact Factor