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

Boopalan T, Arumugam A, Parada J, Saltzstein E, Lakshmanaswamy R - Cancer Sci. (2015)

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.

View Article: PubMed Central - PubMed

Affiliation: Center of Excellence in Cancer Research, Texas Tech University Health Sciences Center, El Paso, Texas, USA.

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Hormone treatment increases nuclear factor-κB (NF-κB) signaling. (a) Western blots indicate the activation of NF-κB subunits p65, p50, cyclin D1, and Bcl2 in mammary tumors treated with estradiol (E), progesterone (P), or mifepristone (M) alone or in combination. (b) Hormone treatment activates NF-κB subunits p65, p50, cyclin D1, and Bcl2 in MCF-7 cells.
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fig07: Hormone treatment increases nuclear factor-κB (NF-κB) signaling. (a) Western blots indicate the activation of NF-κB subunits p65, p50, cyclin D1, and Bcl2 in mammary tumors treated with estradiol (E), progesterone (P), or mifepristone (M) alone or in combination. (b) Hormone treatment activates NF-κB subunits p65, p50, cyclin D1, and Bcl2 in MCF-7 cells.

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).


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

Boopalan T, Arumugam A, Parada J, Saltzstein E, Lakshmanaswamy R - Cancer Sci. (2015)

Hormone treatment increases nuclear factor-κB (NF-κB) signaling. (a) Western blots indicate the activation of NF-κB subunits p65, p50, cyclin D1, and Bcl2 in mammary tumors treated with estradiol (E), progesterone (P), or mifepristone (M) alone or in combination. (b) Hormone treatment activates NF-κB subunits p65, p50, cyclin D1, and Bcl2 in MCF-7 cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4317778&req=5

fig07: Hormone treatment increases nuclear factor-κB (NF-κB) signaling. (a) Western blots indicate the activation of NF-κB subunits p65, p50, cyclin D1, and Bcl2 in mammary tumors treated with estradiol (E), progesterone (P), or mifepristone (M) alone or in combination. (b) Hormone treatment activates NF-κB subunits p65, p50, cyclin D1, and Bcl2 in MCF-7 cells.
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).

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.

View Article: PubMed Central - PubMed

Affiliation: Center of Excellence in Cancer Research, Texas Tech University Health Sciences Center, El Paso, Texas, USA.

Show MeSH
Related in: MedlinePlus