Estrogen receptor status heterogeneity in breast cancer tumor: role in response to endocrine treatment

Tumor heterogeneity affects diagnosis, prognosis and response to therapy. Heterogeneity is found in both normal and neoplastic human mammary gland. Indeed, luminal ER-negative cells can give rise to various phenotypes, including ER-negative and ER-positive mammary tumors. As a result, the tumor phenotype does not necessarily reflects the cell of origin of cancer. With regard to the ER status, heterogeneity can challenge endocrine therapies, where the elimination of responsive clones could lead to reduced treatment efficacy and tumor relapse through the expansion of the resistant clones. The aim of this study was to investigate breast tumor heterogeneity and its role in endocrine resistance onset. For this purpose, we used ER+ (T47D, CAMA1) and triple-negative breast cancer cell lines (TNBC; MDA-MB-231, HCC70), co-cultures using 2D and 3D models. Our results showed that ER status is modulated when ER+ cells are cultured in the presence of TNBC cells, leading to a different response to endocrine therapy, demonstrating that the response to treatment can be affected by the influence that different breast cancer cell types exert on each other. In addition, ER+ positive cells doubling time was modified after exposure to TNBC cell co-culturing. Further experiments are required to fully elucidate the molecular mechanism of these observations.