Gene expression signatures: A tool for analysis of breast cancer prognosis and therapy.

Breast Cancer is the most predominant female cancer in developed as well as developing countries. The treatment strategies of breast cancers depends on an array of factors like age at diagnosis, menstrual status, dietary pattern, immunological response, genetic variations of the cancer cells etc. Recent technological advancements in cancer diagnosis lead to the emergence of gene expression pattern for better understanding of the tumor behavior.

BRCA1 promoter hypermethylation in human placenta: a hidden link with β-hCG expression.

Gestational trophoblastic diseases (GTD) are group of pregnancy-related tumors characterized by abnormal levels of 'β-hCG' with higher incidence in South-East Asia, especially India. Our laboratory has reported that wild-type BRCA1 transcriptionally regulates β-hCG in triple negative breast cancers (TNBCs). These factors culminated into analysis of BRCA1 status in GTD, which would emanate into elucidation of BRCA1- β-hCG relationship and unraveling etio-pathology of GTD.

β-hCG-induced mutant BRCA1 ignites drug resistance in susceptible breast tissue.

β-hCG expression in breast cancer is highly controversial with reports supporting both protective and tumorigenic effects. It has also been reported that risk of breast cancer at an early age is increased with full-term pregnancies if a woman is a BRCA1 mutation carrier. We have already demonstrated that BRCA1-defective cells express high levels of β-hCG and that when BRCA1 is restored, β-hCG level is reduced.

Brcal Defective Breast Cancer Cells Induce in vitro Transformation of Cancer Associated Fibroblasts (CAFs) to Metastasis Associated Fibroblasts (MAF).

It is known that Cancer Associated Fibroblast (CAFs) from the primary tumor site can accompany cancer cells to a secondary site during the process of metastasis. We hypothesize that these CAFs could be transformed to an altered cell type, which can be called as Metastasis Associated Fibroblasts (MAF) in turn can support, and convoy cancer cells for metastasis. There are no published reports that have characterized and distinguished CAFs from MAF.

Proteomic Profiling of β-hCG-Induced Spheres in BRCA1 Defective Triple Negative Breast Cancer Cells.

Previously, we identified that β-hCG is expressed by BRCA1 mutated but not wild type breast cancers in vitro/in vivo and exhibited a novel event in β-hCG overexpressing BRCA1 mutated HCC1937 cells where the cells were able to form spheres (HCC1937 β spheres) in adherent cell culture plates even in the absence of any growth factors. These spheres express stem cell and EMT markers. In the present study, we carried out the total proteomic profiling of these HCC1937 β spheres obtained from BRCA1 defective β-hCG expressing stable breast cancer cells to analyze the cell signaling pathways that are active in these cells.

Selective mode of action of plumbagin through BRCA1 deficient breast cancer stem cells.

Background: Studies over the past decade and half have identified cancer stem cells (CSCs) to be responsible for tumorigenesis, invasion, sustenance of metastatic disease, radio- and chemo-resistance and tumor relapse. Recent reports have described the plasticity of breast CSCs (BCSCs) to shift between the epithelial and mesenchymal phenotypes via Epithelial-Mesenchymal Transition (EMT) and Mesenchymal-Epithelial Transition (MET) states as the reason for their invasive capabilities. Additionally, BRCA1 has been found to be a mammary stem cell fate determinant.

Increased sensitivity of BRCA defective triple negative breast tumors to plumbagin through induction of DNA Double Strand Breaks (DSB).

We have earlier shown that Plumbagin (PB) can induce selective cytotoxicity to BRCA1 defective ovarian cancer cells; however, the effect of this molecule in BRCA1 mutated breast cancers has not been analyzed yet. Here, we report that reactive oxygen species (ROS) induced by PB resulted in DNA DSB and activates downstream signaling by ATR/ATM kinases and subsequent apoptosis. PB reduces DNA- dependent protein kinase (DNA-PK) expression and inhibits NHEJ (Non Homologous End Joining) activity in BRCA1 defective breast cancer cells.

Nitric oxide and reactive oxygen species: Clues to target oxidative damage repair defective breast cancers.

The identification of various biomolecules in cancer progression and therapy has led to the exploration of the roles of two cardinal players, namely Nitric Oxide (NO) and Reactive Oxygen Species (ROS) in cancer. Both ROS and NO display bimodal fashions of functional activity in a concentration dependent manner, by inducing either pro- or anti- tumorigenic signals. Researchers have identified the potential capability of NO and ROS in therapies owing to their role in eliciting pro-apoptotic signals at higher concentrations and their ability to sensitize cancer cells to one another as well as to other therapeutics.