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

• Published in: Cancer science Vol. 106; no. 1; pp. 25 - 33
• Main Authors: Boopalan, Thiyagarajan, Arumugam, Arunkumar, Parada, Jacqueline, Saltzstein, Edward, Lakshmanaswamy, Rajkumar
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.01.2015; BlackWell Publishing Ltd
• Subjects: AKT protein; Animals; Apoptosis; Brain tumors; Breast cancer; Cancer therapies; Carcinogenesis; Carcinogenesis - metabolism; Cell growth; Cell Proliferation; Cyclin D1 - metabolism; Deoxyribonucleic acid; DNA; Estradiol; Estradiol - physiology; Estrogens; Female; Gene Expression Regulation, Neoplastic; Glioma; GLI‐1; Hormone replacement therapy; Humans; Ligands; Mammary Neoplasms, Experimental - metabolism; MCF-7 Cells; Menopause; Mifepristone; NF-kappa B - metabolism; Original; Phenols; Progesterone; Progesterone - physiology; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-bcl-2 - metabolism; RANK Ligand - physiology; RANKL; Rats, Sprague-Dawley; Receptor Activator of Nuclear Factor-kappa B - metabolism; Signal Transduction; Studies; TRANCE protein; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptional Activation; Tumors; Upstream stimulating factor 1; Womens health; Zinc Finger Protein GLI1; St Louis Missouri; United States > US; RANKL; GLI-1; mifepristone; Estradiol; progesterone
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.12571

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‐κB (NF‐κB) 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‐κB (RANK), and NF‐κB 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‐κB, 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. Progesterone induces RANKL in the mammary gland. RANKL activates GLI‐1 transcription factor facilitating mammary carcinogenesis.