title: Receptor activator for nuclear factor-κB ligand signaling promotes progesterone-mediated estrogen-induced mammary carcinogenesis.
abstract: 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.
authors.affiliation: Center of Excellence in Cancer Research, Texas Tech University Health Sciences Center, El Paso, Texas, USA.
authors.forename: Thiyagarajan
authors.initials: T
authors.lastname: Boopalan
authors.forename: Arunkumar
authors.initials: A
authors.lastname: Arumugam
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Parada
authors.forename: Edward
authors.initials: E
authors.lastname: Saltzstein
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Lakshmanaswamy
mesh_terms: D000818:Animals; D017209:Apoptosis; D063646:Carcinogenesis / Q000378:metabolism*; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D004958:Estradiol / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011374:Progesterone / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D053245:RANK Ligand / Q000502:physiology*; D017207:Rats, Sprague-Dawley; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D000071676:Zinc Finger Protein GLI1
chemical_list: C000595707:BCL2 protein, human; C530104:CCND1 protein, human; C400551:GLI1 protein, human; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D019938:Cyclin D1; D011374:Progesterone; D004958:Estradiol; D051057:Proto-Oncogene Proteins c-akt
keywords: Estradiol; GLI-1; RANKL; mifepristone; progesterone