Interplay Between ERK1/2 Signaling Pathway and Estradiol Receptor Modulates ER Targeted Genes Involved in Progression of Estrogen Responsive Breast Cancers.

Abstract

Breast cancer is a leading global health concern, while the endocrine resistance in breast cancer poses a critical challenge, directly undermining the long-term effectiveness of hormone therapies and significantly impacting patient survival and treatment outcomes. Hence, the present study aims to elucidate the non-genomic mechanism of ERK1/2 signalling pathway, in conjunction with ER and GPR30 receptors involved in regulation of breast cancer progression in MCF-7 and T47D cells. We assessed cell proliferation using MTT and Trypan blue assays, expression studies by reverse transcription quantitative PCR and western blot analysis, the migratory abilities of cells by scratch-wound healing assay. Our results revealed significant down (90%) regulation of E2-induced ERK phosphorylation, inturn suppression of proliferation rate by 30% and migration by 35% using small molecular inhibitors of ERK in MCF-7 and T47D cells confirming ERK as the central direct target for breast cancer proliferation and development. Collectively, our results suggest that E2-induced 1.5-fold upregulation of phospho ERK1/2 expression promotes breast cancer cell proliferation and migration via a Src/EGFR/ERK pathway. These findings provide a novel strategy of combining endocrine therapy with targeted agents (ERK inhibitors), a cornerstone in managing endocrine-resistant condition, delaying progression and improving outcomes in the treatment of breast cancer.