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: Ovarian hormone treatments increased AKT phosphorylation in MCF-7 cells and in ACI rat mammary tumors (Fig.3). Mifepristone completely abrogated the AKT phosphorylation and inhibited cell proliferation both in vitro and in vivo (Figs3,S2e,f). RANKL overexpression in MCF-7 cells also increased phosphorylation of AKT (Figs6a,S3a). Next, we tested the respective abilities of four unique 29-mer shRNAs and a scrambled 29-mer control shRNA to silence RANKL in MCF-7 cells. We selected the shRNA that was the most effective in silencing RANKL (Fig. S4). We found that silencing RANKL with the shRNA attenuated the phosphorylation of AKT (Figs6b,S3b). Because AKT supports cell survival through the activation of NF-κB,23,24 we tested whether the progesterone-mediated activation of RANKL results in the activation of NF-κB. All the hormone treatments resulted in the increased expression levels of NF-κB subunits p50 and p65, both in MCF-7 cells and in rat mammary tumors (Figs7,S4d,e,S5d,e). In contrast, mifepristone significantly downregulated the expression of NF-κB subunits p50 and p65, both in MCF-7 cells and in rat mammary tumors (Figs7,S5a–d). Likewise, overexpression of RANKL increased the expression of NF-κB subunits p50 and p65 (Figs6a,S3c,d); silencing suppressed the activation of the NF-κB subunits (Figs6b,S3e,f).
Affiliation: Center of Excellence in Cancer Research, Texas Tech University Health Sciences Center, El Paso, Texas, USA.