SMADs as a Driver of TGF – B Mediated Signaling during Antiestrogen Treatment in Triple Negative Breast Cancer

Abstract

Triple Negative Breast Cancer (TNBC) is a complex heterogeneous disease characterized by the absence of Estrogen Receptor (ER-), Progesterone Receptor (PR-), and HER-2 receptor (HER-2-). It represents approximately 15-20% of all breast cancer cases and believed to have aggressive phenotype and poor prognosis. Currently no adjuvant intervention is procurable for treating TNBC patients. Due to heterogeneity of this cancer subtype, there has been a major limitation to targeted therapy. In TNBC, because of absence of hormone receptors, antiestrogens which are meant to mimic the action of hormone thereafter cannot be used as target for treatment purpose. Therefore, the need for molecular prognostic markers is emerging. There are two areas yet to be explored: Lack of adjuvant treatment for triple negative breast tumors and non-responsiveness of antiestrogen. Many tumor markers such as growth factors, signaling proteins, transcription factors are reported to be under clinical trials so as to find their utility for therapeutic purpose. TGF-β is one of those potential biomarkers which play a crucial role during breast tumorigenesis. The ability of TGF-β as an immunosuppressant has been reported to be a possible index to breast tumour progression. However, it has been reported that on activating alternate pathway may increase the effectiveness of antiestrogen in TNBC cells. This might further help to establish a crosstalk between Estrogen Receptor (ER) and TGF-β signaling through SMADs. Wherein in SMAD-dependent TGF-β signaling, SMAD-3 gets phosphorylated and binds with co-SMAD (SMAD-4) and forms a SMAD complex, which thereby enters the nucleus and initiates transcriptional activity. The prime focus of our study was to find out the possibilities of the usefulness of antiestrogens as potential drug targets using Tamoxifen and its active metabolite 4-OH-Tamoxifen for TNBC cell lines (MDA-MB-468 and MDA-MB-231). Tamoxifen is primarily a selective modulator of the ER pathway. SMADs are primary intracellular signaling molecules that mediate the TGF-β signaling pathway. In the current study, we have evaluated the phenotypic expression of TGF-β mediated signaling mediators during the antiestrogen treatment in TNBC cells (MDA-MB-468 and MDA-MB-231 cell lines).