Natural and synthetic progestins enrich cancer stem cell-like cells in hormone-responsive human breast cancer cell populations in vitro

Sandy Goyette,1,2 Yayun Liang,1,2 Benford Mafuvadze,1,2 Matthew T Cook,1,2 Moiz Munir,1,2 Salman M Hyder1,2 1Department of Biomedical Sciences, 2Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA Abstract: Clinical trials and studies have shown that combination estrogen...

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Autores principales:	Goyette S, Liang Y, Mafuvadze B, Cook MT, Munir M, Hyder SM
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2017
Materias:	breast cancer progestins medroxyprogesterone acetate cancer stem cells CD44 ALDH Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/e7e1e7f8a244492e83730a56904c229b
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spelling	oai:doaj.org-article:e7e1e7f8a244492e83730a56904c229b2021-12-02T07:07:53ZNatural and synthetic progestins enrich cancer stem cell-like cells in hormone-responsive human breast cancer cell populations in vitro1179-1314https://doaj.org/article/e7e1e7f8a244492e83730a56904c229b2017-05-01T00:00:00Zhttps://www.dovepress.com/natural-and-synthetic-progestins-enrich-cancer-stem-cell-like-cells-in-peer-reviewed-article-BCTThttps://doaj.org/toc/1179-1314Sandy Goyette,1,2 Yayun Liang,1,2 Benford Mafuvadze,1,2 Matthew T Cook,1,2 Moiz Munir,1,2 Salman M Hyder1,2 1Department of Biomedical Sciences, 2Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA Abstract: Clinical trials and studies have shown that combination estrogen/progestin hormone replacement therapy, but not estrogen therapy alone or placebo, increases breast cancer risk in postmenopausal women. Using animal models, we have previously shown that both natural and synthetic progestins (including medroxyprogesterone acetate [MPA], a synthetic progestin used widely in the clinical setting) accelerate the development of breast tumors in vivo and increase their metastasis to lymph nodes. Based on these observations, we have hypothesized that progestin-induced breast cancer tumor growth and metastasis may be mediated by an enrichment of the cancer stem cell (CSC) pool. In this study, we used T47-D and BT-474 hormone-responsive human breast cancer cells to examine the effects of progestin on phenotypic and functional markers of CSCs in vitro. Both natural and synthetic progestins (10 nM) significantly increased protein expression of CD44, an important CSC marker in tumor cells. MPA increased the levels of both CD44 variants v3 and v6 associated with stem cell functions. This induction of CD44 was blocked by the antiprogestin RU-486, suggesting that this process is progesterone receptor (PR) dependent. CD44 induction was chiefly progestin dependent. Because RU-486 can bind other steroid receptors, we treated PR-negative T47-DCO-Y cells with MPA and found that MPA failed to induce CD44 protein expression, confirming that PR is essential for progestin-mediated CD44 induction in T47-D cells. Further, MPA treatment of T47-D cells significantly increased the activity of aldehyde dehydrogenase (ALDH), another CSC marker. Finally, two synthetic progestins, MPA and norethindrone, significantly increased the ability of T47-D cells to form mammospheres, suggesting that enrichment of the CD44high, ALDHbright subpopulation of cancer cells induced by MPA exposure is of functional significance. Based on our observations, we contend that exposure of breast cancer cells to synthetic progestins leads to an enrichment of the CSC pool, supporting the development of progestin-accelerated tumors in vivo. Keywords: breast cancer, progestins, medroxyprogesterone acetate, cancer stem cells, CD44, ALDHGoyette SLiang YMafuvadze BCook MTMunir MHyder SMDove Medical Pressarticlebreast cancerprogestinsmedroxyprogesterone acetatecancer stem cellsCD44ALDHNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENBreast Cancer: Targets and Therapy, Vol Volume 9, Pp 347-357 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	breast cancer progestins medroxyprogesterone acetate cancer stem cells CD44 ALDH Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	breast cancer progestins medroxyprogesterone acetate cancer stem cells CD44 ALDH Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Goyette S Liang Y Mafuvadze B Cook MT Munir M Hyder SM Natural and synthetic progestins enrich cancer stem cell-like cells in hormone-responsive human breast cancer cell populations in vitro
description	Sandy Goyette,1,2 Yayun Liang,1,2 Benford Mafuvadze,1,2 Matthew T Cook,1,2 Moiz Munir,1,2 Salman M Hyder1,2 1Department of Biomedical Sciences, 2Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA Abstract: Clinical trials and studies have shown that combination estrogen/progestin hormone replacement therapy, but not estrogen therapy alone or placebo, increases breast cancer risk in postmenopausal women. Using animal models, we have previously shown that both natural and synthetic progestins (including medroxyprogesterone acetate [MPA], a synthetic progestin used widely in the clinical setting) accelerate the development of breast tumors in vivo and increase their metastasis to lymph nodes. Based on these observations, we have hypothesized that progestin-induced breast cancer tumor growth and metastasis may be mediated by an enrichment of the cancer stem cell (CSC) pool. In this study, we used T47-D and BT-474 hormone-responsive human breast cancer cells to examine the effects of progestin on phenotypic and functional markers of CSCs in vitro. Both natural and synthetic progestins (10 nM) significantly increased protein expression of CD44, an important CSC marker in tumor cells. MPA increased the levels of both CD44 variants v3 and v6 associated with stem cell functions. This induction of CD44 was blocked by the antiprogestin RU-486, suggesting that this process is progesterone receptor (PR) dependent. CD44 induction was chiefly progestin dependent. Because RU-486 can bind other steroid receptors, we treated PR-negative T47-DCO-Y cells with MPA and found that MPA failed to induce CD44 protein expression, confirming that PR is essential for progestin-mediated CD44 induction in T47-D cells. Further, MPA treatment of T47-D cells significantly increased the activity of aldehyde dehydrogenase (ALDH), another CSC marker. Finally, two synthetic progestins, MPA and norethindrone, significantly increased the ability of T47-D cells to form mammospheres, suggesting that enrichment of the CD44high, ALDHbright subpopulation of cancer cells induced by MPA exposure is of functional significance. Based on our observations, we contend that exposure of breast cancer cells to synthetic progestins leads to an enrichment of the CSC pool, supporting the development of progestin-accelerated tumors in vivo. Keywords: breast cancer, progestins, medroxyprogesterone acetate, cancer stem cells, CD44, ALDH
format	article
author	Goyette S Liang Y Mafuvadze B Cook MT Munir M Hyder SM
author_facet	Goyette S Liang Y Mafuvadze B Cook MT Munir M Hyder SM
author_sort	Goyette S
title	Natural and synthetic progestins enrich cancer stem cell-like cells in hormone-responsive human breast cancer cell populations in vitro
title_short	Natural and synthetic progestins enrich cancer stem cell-like cells in hormone-responsive human breast cancer cell populations in vitro
title_full	Natural and synthetic progestins enrich cancer stem cell-like cells in hormone-responsive human breast cancer cell populations in vitro
title_fullStr	Natural and synthetic progestins enrich cancer stem cell-like cells in hormone-responsive human breast cancer cell populations in vitro
title_full_unstemmed	Natural and synthetic progestins enrich cancer stem cell-like cells in hormone-responsive human breast cancer cell populations in vitro
title_sort	natural and synthetic progestins enrich cancer stem cell-like cells in hormone-responsive human breast cancer cell populations in vitro
publisher	Dove Medical Press
publishDate	2017
url	https://doaj.org/article/e7e1e7f8a244492e83730a56904c229b
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Natural and synthetic progestins enrich cancer stem cell-like cells in hormone-responsive human breast cancer cell populations in vitro

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