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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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Western blot analysis of receptor activator for nuclear factor-κB ligand (RANKL)/receptor activator for nuclear factor-κB (RANK) signaling in MCF-7 cells and ACI mammary tumors. (a) Expression of RANKL, RANK, phosphorylated protein kinase B (pAKT) and AKT in MCF-7 cells treated with estradiol (E), progesterone (P), or mifepristone (M) alone or in combination for 24 h. (b) Expression of RANKL, RANK, pAKT, and AKT in mammary tumors treated with hormones for 36 weeks.
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fig03: Western blot analysis of receptor activator for nuclear factor-κB ligand (RANKL)/receptor activator for nuclear factor-κB (RANK) signaling in MCF-7 cells and ACI mammary tumors. (a) Expression of RANKL, RANK, phosphorylated protein kinase B (pAKT) and AKT in MCF-7 cells treated with estradiol (E), progesterone (P), or mifepristone (M) alone or in combination for 24 h. (b) Expression of RANKL, RANK, pAKT, and AKT in mammary tumors treated with hormones for 36 weeks.

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.


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)

Western blot analysis of receptor activator for nuclear factor-κB ligand (RANKL)/receptor activator for nuclear factor-κB (RANK) signaling in MCF-7 cells and ACI mammary tumors. (a) Expression of RANKL, RANK, phosphorylated protein kinase B (pAKT) and AKT in MCF-7 cells treated with estradiol (E), progesterone (P), or mifepristone (M) alone or in combination for 24 h. (b) Expression of RANKL, RANK, pAKT, and AKT in mammary tumors treated with hormones for 36 weeks.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig03: Western blot analysis of receptor activator for nuclear factor-κB ligand (RANKL)/receptor activator for nuclear factor-κB (RANK) signaling in MCF-7 cells and ACI mammary tumors. (a) Expression of RANKL, RANK, phosphorylated protein kinase B (pAKT) and AKT in MCF-7 cells treated with estradiol (E), progesterone (P), or mifepristone (M) alone or in combination for 24 h. (b) Expression of RANKL, RANK, pAKT, and AKT in mammary tumors treated with hormones for 36 weeks.
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.

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