Infiltrating mast cell-mediated stimulation of estrogen receptor activity in breast cancer cells promotes the luminal phenotype

Abstract

Tumor growth and development is determined by both cancer cell-autonomous and microenvironmental mechanisms, including the contribution of infiltrating immune cells. Since the role of mast cells (MC) in this process is poorly characterized and even controversial, we investigated their part in breast cancer (BC). Crossing C57BL/6 MMTV-PyMT mice, which spontaneously develop mammary carcinomas, with MC-deficient C57BL/6-KitW-sh/W-sh (Wsh) mice, showed that MC promote tumor growth and prevent the development of basal CK5-positive areas in favor of a luminal gene program. When co-cultured with BC cells in vitro, MC hindered activation of cMET, a master regulator of the basal program, and simultaneously promoted expression and activation of estrogen receptor (ESR1/ER) and its target genes (PGR, KRT8/CK8, BCL2), which are all luminal markers. Moreover, MC reduced ERBB2/HER2 levels, whose inhibition further increased ESR1 expression. In vivo and in silico analysis of BC patients revealed a direct correlation between MC density and ESR1 expression. In mice engrafted with HER2-positive BC tumors, co-injection of MC increased tumor engraftment and outgrowth, supporting the link between MC and increased risk of relapse in BC patients. Together our findings support the notion that MC influence the phenotype of BC cells by stimulating a luminal phenotype and ultimately modifying the outcome of the disease.