Lanterna Rally

Author: Sneha Tirumani Pandithar

Publisher:

Published: 2021

Total Pages: 43

ISBN-13:

Breast cancer is currently targeted using various endocrine therapies that include use of Selective Estrogen Receptor modulators (SERM), Selective Estrogen Receptor Down Regulator (SERD) and Aromatase inhibitors (AI). Tamoxifen (TAM) is a primary choice in treating early-stage estrogen receptor positive breast cancer in post-menopausal women. Despite the proven therapeutic efficacy and safety profile of TAM as a SERM, resistance to the drug and reoccurrence of tumor appears to be a complication that many patients deal with. Molecular pathways underlying the development of resistance are being widely studied. The tumor microenvironment is perceived to play a vital role in multiple stages of disease progression, development of resistance and immune-escaping ability. However, the role of the tumor microenvironment in endocrine resistant breast cancer needs to be investigated. Our previous work shows that the critical molecular and cellular components secreted from a crosstalk between breast cancer cells and stromal cells can regulate tumor growth and the process of metastasis in breast cancer. We have established four different tamoxifen resistant breast cancer (TAMR) cells to simulate pre- and post-menopausal conditions. We screened the secreted factors from normal fibroblast co-cultured with TAMR cells using cytokine antibody arrays targeting 105 cytokines simultaneously and ranked the expression of each of the cytokines using real time qPCR. CXCL1 and IL-6 were our top candidates, which we further confirmed using U-Plex (MSD) assay. Our data showed increased proliferation of TAMR cells co-cultured with fibroblasts when compared to monoculture. To study the role of the cytokines in metastasis we examined cell migration of TAMR cells. TAMR cell migration, a key step in tumor metastasis, was promoted by conditioned medium (CM) from TCM-induced fibroblasts. Furthermore, inhibition of the CXCL1 and IL-6 signaling pathway by Reparixin, an inhibitor of the CXCL1 receptor CXCR1/2, and Tocilizumab, an inhibitor of the IL-6 receptor yielded diminished growth and migration of the TAMR cells.We have also been able to show that reparixin affects the phosphorylation of the ERK in fibroblasts and treatment with reparixin has been affecting the viability of TAMR cells. These findings have identified the key regulators in endocrine resistant breast cancer and support our hypothesis that CXCL1 signaling pathways support the tumor cells to bypass endocrine therapy. In this project we have been able to identify the key signaling pathways that may be activated by these cytokines and determine a therapeutic strategy that could alter such activation and induce cell death.