Research Summary

The global scenario rates Breast Cancer to be the second most prevalent cancer among women, after skin cancer, representing 16% of all the female cancers. Nevertheless, an effective chemotherapeutic agent either for the prevention or cure of this deadly disease has not been identified yet. Of the germline mutations in BRCA1 identified, 50% cases contribute to hereditary breast cancers and approximately 80% of the cases result in hereditary breast and ovarian cancers. Decreased BRCA1 expression due to hypermethylation of the BRCA1 promoter or the loss of BRCA1 allele has been reported in 30 - 40% of sporadic breast cancers as well. Thus BRCA1 plays a cardinal role in the breast cancer development. Triple negative breast (TNB) tumors, which accounts for 15% of the breast cancers, frequently harbor homologous recombination (HR) defects due to BRCA1 dysfunction. Even though the evidences suggest that platinated agents are best suited chemotherapeutic targets in TNB's with HR deficiency, there is a safety concern regarding the side effects of these intercalators due to their non targeted behavior and the increased cases of relapse after the chemotherapy. The DNA repair defect characteristic of BRCA1 deficient cells confers sensitivity to PARP inhibitors as monotherapeutic targets or with platinated drugs as combination agents. One of the main focuses of our lab is in identification of novel molecules to target BRCA1 deficient tumors.
Our lab also focuses on analyzing the role of BRCA1 in human mammary stem cell fate using in vitro systems and has found that BRCA1 defect increases the stem-like behavior in the normal human mammary cells, thus BRCA1 is a regulator of mammary stem cell fate. It has been reported that the mouse mammary tumors induced by the conditional deletion of BRCA1 results in the eventual drug resistance after their initial response to doxorubicin or docetaxel therapy and this phenomenon is due to the existence of cellular sub-compartment within the tumor which possess a subset of cells with stem-like behavior. These cells if isolated and characterized may provide a useful model for drug development for improvement of the existing treatment regimes.
Prostate is the most consistently reported site for cancer susceptibility in male carriers of BRCA1 mutation. The rate of increase in the incidence of prostate cancer but isn't paralleled by the exploration of their etiology or their risk. Hence their optimal clinical management regimes are not yet defined. We try to analyze the effect of certain drugs in the prostate cancer cells with regard to BRCA1/2 presence and absence.
Recent studies indicate that the tumor progression is characterized by local accumulation of extracellular matrix components and connective tissue cells surrounding the tumor cluster, a phenomenon termed as the tumor-stroma interaction. The presence of Cancer Associated Fibroblasts (CAFs), one of the major tumor stroma components, seem to be a necessary requirement for the growth and dissemination of several tumor cells since they secrete proteins that may stimulate adhesion, motility and escape from the local growth control as well as angiogenesis. Our research interest encompasses involvement of tumor microenvironment particularly CAF, on tumor invasion and metastasis. By studying the effect of CAFs on cancer cells, the main aim is to understand the possible role of the stromal components in the development and the invasive nature of breast cancer.