Evaluating the Crosstalk of TGF-β Signaling Pathway with HER2 Signaling Pathway and Estrogen Receptor Signaling Pathway

Abstract

Breast cancer is the most common cancer in women worldwide and remains an important global health issue. Current Breast Cancer Management revolve around targeting the Hormone receptors namely Estrogen receptor (ER) & Progesterone Receptor (PR) and Growth Factor receptor namely HER-2 Receptor (Human Epidermal Growth Factor Receptor-2). Antiestrogen Therapies using Tamoxifen and other hormone antagonists have been successful in treating hormone-sensitive Breast Cancers worldwide. However 33% of patients receiving hormonal therapy show non-responsiveness or resistance towards antiestrogens chiefly Tamoxifen. Studies indicate a possible role in mediating non-responsiveness or resistance towards antiestrogens is by increased levels of Transforming Growth Factor – β (TGF-β). Therefore we aim to determine the expression of TGF-β1, TGF-β2 and its signaling mediator SMAD-3 and SMAD-4 by ELISA so as to establish a crosstalk between the TGF-β pathway and the ER pathway. Along with the above study our work is also aimed at HER-2 positive Breast cancer. 25% of ER-PR- negative breast tumors are usually HER-2 positive and believed to show no response against antihormonal therapies. HER-2 positive Breast cancer are more aggressive than HER-2 negative Breast Cancers. Evidences suggest that there exist a crosstalk between the HER-2 signaling pathway and TGF-β pathway. HER-2 Signaling prevents apoptosis by inhibiting activity of FoxO and increases growth and proliferation by activating Akt signaling molecule through the PI3K/Akt Pathway. It has been shown that Akt molecule inhibits the activity of SMAD-3, a signaling mediator in TGF-β pathway. In the current study, by determining the phenotypic expression of TGF-β1, TGF-β2 and its signaling mediator SMAD-3 and SMAD-4 by ELISA, we aim to evaluate the crosstalk between TGF-β pathway and HER-2 Signaling Pathway. In addition we would like to establish the role of TGF-β during Anti-estrogen treatment. Moreover we are trying to establish utility of TGF-β as in independent biomarker.