Estradiol, the female sex steroid is involved in numerous physiological processes. Estradiol brings about its action via binding to the estrogen receptor (ER), either nuclear,cytosolic or plasma membrane localized. Selective estrogen receptor modulators (SERMs) are ER ligands that display an unusual tissue selective agonistic or antagonistic pharmacology. Indeed a major hope for SERMs is that they will mimic estrogens critical benefits for the bones and heart but will act as antiestrogenic in the breast and uterus, thus avoiding estrogenic harmful effects in these tissues. Based on this I am pursuing several different approaches to understand the molecular basis of ER function and how ER activity can be manipulated in a selective fashion by dietary estrogens to positively impact human health. I am analyzing the SERM activity of Punica granatum (Pomegranate) extracts in a panel of cell lines. I also intend to identify the active compounds of the extracts and thorough analysis of its antiestrogenic properties in vivo to demonstrate its suitability as an SERM.

The steroid hormone estrogen causes its multitude effects through estrogen receptors that mediate the transcription of number of genes involved in reproduction, metabolism, growth and differentiation.. It has been widely established that flavonoids, a group of polyphenolic phytochemicals can exert various biological effects including anti-oxidant, anti-carcinogenic, anti-inflammatory and also modulate the function of sex hormones and their receptors. Experimental studies have also revealed that these components regulate the molecules in the cell signaling transduction pathways, including NF-?B, MAPK, p53, AR and ER pathways. It is hypothesized that by modulating signaling pathways chemo preventive agents activate cell death signals and induce apoptosis in cancer cells resulting in the inhibition of cancer development or progression. More in depth in vitro and in vivo studies are required before reaching a conclusion regarding the potential health benefits of these plant derived compounds and its use as chemo preventive agents against hormone dependant cancers. In this study I am focusing on finding out flavonoids with potential estrogenic activities, elucidating the molecular mechanisms of action of individual phytoestrogens and its use against hormone dependant cancers giving emphasis to estrogen receptor mediated pathways.

Breast cancer is the most common female cancers worldwide and the second most common in India. It is increasingly recognized as a heterogeneous disease exhibiting substantial differences with regard to biological behaviour. Steroid hormone receptors (HR) such as estrogen receptor (ER) and progesterone receptor (PgR) in concert with the oncogene ErbB-2/human epidermal growth factor receptor 2 (Her2) are critical determinants of the breast cancer subtypes. In recent years, molecular classifications have been done to categorize breast cancer based on gene expression profiling. Five common subgroups have emerged, two of which arise from estrogen receptor-positive tumors (Luminal A and Luminal B), and three from estrogen receptor-negative tumors (basal-like, HER2-positive and normal breast like). The ‘‘basal-like’’ category of tumors is composed almost entirely of ‘‘triple-negative’’ breast cancers (TNBC) [i.e., tumors that are negative for ERs, PgRs, and Her2]. This phenotype appears to have a more aggressive course than other breast cancers, with less response to standard treatment, shorter disease-free survival and overall survival (OS) times. In addition, features such as tumor microenvironment and activity of miRNAs affect the proliferation, survival and treatment outcome of the disease. My study proposes to sub-classify triple negative breast cancer, further understand the influence of microenvironment on its aggressive phenotype and elucidate its clinical biology.

C-type natriuretic peptide (CNP) is a vasodilator produced by the vascular endothelium. Plasminogen activator inhibitor (PAI-1) plays a major role in the process of fibrinolysis and CNP is reported to reduce PAI-1 expression in human endothelial cells. Estradiol is known to induce CNP gene expression in Rabbit uterus. This observation suggests that deficiency of estradiol in post menopause age increases risk for atherosclerosis by reduced CNP and loss of subsequent downstream signaling. So it is proposed to test the hypothesis that whether estradiol modulates CNP and PAI-1 balance in diseased blood vessels as seen in post menopause woman.

Owing to a heightened awareness of the adverse effects of hormone replacement therapy, prompted by the Women’s health initiative study, the search for alternative treatments has intensified. Epidemiological studies suggest that consumption of diets containing fruits and vegetables rich for polyphenols may reduce the risk of developing a variety of cancers. Estrogen replacement therapy is approved for the prevention of various problems associated with the postmenopausal women. However in post menopausal conditions, use of estrogen is limited due to its numerous undesirable side effects such as uterine and breast cancer. Phytoestrogens are secondary metabolites produced in a wide variety of plants that induce biologic responses in vertebrates and can mimic or modulate the actions of endogenous estrogens, usually by binding to estrogen receptors. It is found in a wide number of plants. Hence it would be most helpful to explore naturally occurring substances especially of plant origin that could prevent adverse side effects. The present project proposal has two sections 1. conducting a survey for getting the information of the Ethno Botanicals and its documentation and 2. testing of its phytoestrogenic activities as well as their efficacy in estrogen positive breast cancer cell lines.

Among thyroid cancers, papillary carcinoma is the most common endocrine malignancy (>70%). The tumour typically arises as an irregular, solid or cystic mass from normal thyroid tissue. The incidences of thyroid malignancies are about 3 times more frequent in females than in males, indicating a role of endocrine factors in thyroid cancer. Even though papillary cancer has a relatively high cure rate, the presence of lymph node metastasis in the cervical areas causes a higher recurrence rate. A few reports suggest the role of estrogen in contributing to the metastatic phenotype of papillary thyroid cancer. The molecular mechanism by which estrogen modulates the growth and metastatic propensity of thyroid cancer cells, however remains to be elucidated. My work is to delineate the molecular mechanism of endocrine regulation of papillary thyroid cancer cells. The proposed study may be expected to significantly improve our understanding about papillary thyroid malignancies and help to develop new therapeutic strategies.