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Receptor activator for nuclear factor-?B 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-?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.

SUBMITTER: Boopalan T 

PROVIDER: S-EPMC4317778 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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

Boopalan Thiyagarajan T   Arumugam Arunkumar A   Parada Jacqueline J   Saltzstein Edward E   Lakshmanaswamy Rajkumar R  

Cancer science 20150101 1


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-induce  ...[more]

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