Receptor activator for nuclear factor-κB ligand signaling promotes progesterone-mediated estrogen-induced mammary carcinogenesis.
Bottom Line: In ACI rats, mifepristone significantly reduced the incidence of mammary tumors.Likewise, mifepristone also inhibited the proliferation of 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.
Affiliation: Center of Excellence in Cancer Research, Texas Tech University Health Sciences Center, El Paso, Texas, USA.Show MeSH
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Mentions: We assessed the effects of hormone treatment on RANKL/RANK expression in MCF-7 cells and in ACI rat mammary tumors. Estradiol and progesterone, both separately and in combination, increased RANKL and RANK expression in MCF-7 cells (Figs3a,S2a,b) and mammary tumors (Fig.3b). Mifepristone inhibited RANKL and RANK expression in MCF-7 cells (Fig.3a) and mammary tumors (Figs3b,S2c,d). Furthermore, immunofluorescence in MCF-7 cells (Fig.4a) and immunohistochemical staining in mammary tumors (Fig.4b) confirmed that combined treatment with estradiol and progesterone resulted in a synergistic increase in RANKL/RANK expression compared with either single hormone treatment. Almost 60% of the human breast tumors were estrogen and progesterone receptor positive and of luminal A subtype. We had a small portion of breast tumors that overexpressed human epidermal growth factor receptor-2 (∼25%) and the rest were basal type (∼15%). Immunohistochemical examination of 53 human primary tumors revealed that 86.4% of tumors expressed higher levels of RANKL in cancerous tissue than in normal ducts (Fig.5). RANKL was mainly expressed in the cell surface and cytoplasm.
Affiliation: Center of Excellence in Cancer Research, Texas Tech University Health Sciences Center, El Paso, Texas, USA.