Receptor activator for nuclear factor-κB ligand signaling promotes progesterone-mediated estrogen-induced mammary carcinogenesis

Breast cancer is a leading cause of cancer-related death in women. Prolonged exposure to the ovarian hormones estrogen and progesterone increases the risk of breast cancer. Although estrogen is known as a primary factor in mammary carcinogenesis, very few studies have investigated the role of progesterone. Receptor activator for nuclear factor-B (NF-B) ligand (RANKL) plays an important role in progesterone-induced mammary carcinogenesis. However, the molecular mechanism underlying RANKL-induced mammary carcinogenesis remains unknown. In our current study, we show that RANKL induces glioma-associated oncogene homolog 1 (GLI-1) in estrogen-induced progesterone-mediated mammary carcinogenesis. In vivo experiments were carried out using ACI rats and in vitro experiments were carried out in MCF-7 cells. In ACI rats, mifepristone significantly reduced the incidence of mammary tumors. Likewise, mifepristone also inhibited the proliferation of MCF-7 cells. Hormone treatments induced RANKL, receptor activator of NF-B (RANK), and NF-B in a protein kinase B-dependent manner and inhibited apoptosis by activation of anti-apoptotic protein Bcl2 in mammary tumors and MCF-7 cells. Mechanistic studies in MCF-7 cells reveal that RANKL induced upstream stimulatory factor-1 and NF-B, resulting in subsequent activation of their downstream target GLI-1. We have identified that progesterone mediates estrogen-induced mammary carcinogenesis through activation of GLI-1 in a RANKL-dependent manner.