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Human Breast Progenitor Cell Numbers Are Regulated by WNT and TBX3

BACKGROUND: Although human breast development is mediated by hormonal and non-hormonal means, the mechanisms that regulate breast progenitor cell activity remain to be clarified. This limited understanding of breast progenitor cells has been due in part to the lack of appropriate model systems to de...

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Autores principales: Arendt, Lisa M., St. Laurent, Jessica, Wronski, Ania, Caballero, Silvia, Lyle, Stephen R., Naber, Stephen P., Kuperwasser, Charlotte
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4211891/
https://www.ncbi.nlm.nih.gov/pubmed/25350852
http://dx.doi.org/10.1371/journal.pone.0111442
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author Arendt, Lisa M.
St. Laurent, Jessica
Wronski, Ania
Caballero, Silvia
Lyle, Stephen R.
Naber, Stephen P.
Kuperwasser, Charlotte
author_facet Arendt, Lisa M.
St. Laurent, Jessica
Wronski, Ania
Caballero, Silvia
Lyle, Stephen R.
Naber, Stephen P.
Kuperwasser, Charlotte
author_sort Arendt, Lisa M.
collection PubMed
description BACKGROUND: Although human breast development is mediated by hormonal and non-hormonal means, the mechanisms that regulate breast progenitor cell activity remain to be clarified. This limited understanding of breast progenitor cells has been due in part to the lack of appropriate model systems to detect and characterize their properties. METHODS: To examine the effects of WNT signaling and TBX3 expression on progenitor activity in the breast, primary human mammary epithelial cells (MEC) were isolated from reduction mammoplasty tissues and transduced with lentivirus to overexpress WNT1 or TBX3 or reduce expression of their cognate receptors using shRNA. Changes in progenitor activity were quantified using characterized assays. We identified WNT family members expressed by cell populations within the epithelium and assessed alterations in expression of WNT family ligands by MECs in response to TBX3 overexpression and treatment with estrogen and progesterone. RESULTS: Growth of MECs on collagen gels resulted in the formation of distinct luminal acinar and basal ductal colonies. Overexpression of TBX3 in MECs resulted in increased ductal colonies, while shTBX3 expression diminished both colony types. Increased WNT1 expression led to enhanced acinar colony formation, shLRP6 decreased both types of colonies. Estrogen stimulated the formation of acinar colonies in control MEC, but not shLRP6 MEC. Formation of ductal colonies was enhanced in response to progesterone. However, while shLRP6 decreased MEC responsiveness to progesterone, shTBX3 expression did not alter this response. CONCLUSIONS: We identified two phenotypically distinguishable lineage-committed progenitor cells that contribute to different structural elements and are regulated via hormonal and non-hormonal mechanisms. WNT signaling regulates both types of progenitor activity. Progesterone favors the expansion of ductal progenitor cells, while estrogen stimulates the expansion of acinar progenitor cells. Paracrine WNT signaling is stimulated by estrogen and progesterone, while autocrine WNT signaling is induced by the embryonic T-box transcription factor TBX3.
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spelling pubmed-42118912014-11-05 Human Breast Progenitor Cell Numbers Are Regulated by WNT and TBX3 Arendt, Lisa M. St. Laurent, Jessica Wronski, Ania Caballero, Silvia Lyle, Stephen R. Naber, Stephen P. Kuperwasser, Charlotte PLoS One Research Article BACKGROUND: Although human breast development is mediated by hormonal and non-hormonal means, the mechanisms that regulate breast progenitor cell activity remain to be clarified. This limited understanding of breast progenitor cells has been due in part to the lack of appropriate model systems to detect and characterize their properties. METHODS: To examine the effects of WNT signaling and TBX3 expression on progenitor activity in the breast, primary human mammary epithelial cells (MEC) were isolated from reduction mammoplasty tissues and transduced with lentivirus to overexpress WNT1 or TBX3 or reduce expression of their cognate receptors using shRNA. Changes in progenitor activity were quantified using characterized assays. We identified WNT family members expressed by cell populations within the epithelium and assessed alterations in expression of WNT family ligands by MECs in response to TBX3 overexpression and treatment with estrogen and progesterone. RESULTS: Growth of MECs on collagen gels resulted in the formation of distinct luminal acinar and basal ductal colonies. Overexpression of TBX3 in MECs resulted in increased ductal colonies, while shTBX3 expression diminished both colony types. Increased WNT1 expression led to enhanced acinar colony formation, shLRP6 decreased both types of colonies. Estrogen stimulated the formation of acinar colonies in control MEC, but not shLRP6 MEC. Formation of ductal colonies was enhanced in response to progesterone. However, while shLRP6 decreased MEC responsiveness to progesterone, shTBX3 expression did not alter this response. CONCLUSIONS: We identified two phenotypically distinguishable lineage-committed progenitor cells that contribute to different structural elements and are regulated via hormonal and non-hormonal mechanisms. WNT signaling regulates both types of progenitor activity. Progesterone favors the expansion of ductal progenitor cells, while estrogen stimulates the expansion of acinar progenitor cells. Paracrine WNT signaling is stimulated by estrogen and progesterone, while autocrine WNT signaling is induced by the embryonic T-box transcription factor TBX3. Public Library of Science 2014-10-28 /pmc/articles/PMC4211891/ /pubmed/25350852 http://dx.doi.org/10.1371/journal.pone.0111442 Text en © 2014 Arendt et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Arendt, Lisa M.
St. Laurent, Jessica
Wronski, Ania
Caballero, Silvia
Lyle, Stephen R.
Naber, Stephen P.
Kuperwasser, Charlotte
Human Breast Progenitor Cell Numbers Are Regulated by WNT and TBX3
title Human Breast Progenitor Cell Numbers Are Regulated by WNT and TBX3
title_full Human Breast Progenitor Cell Numbers Are Regulated by WNT and TBX3
title_fullStr Human Breast Progenitor Cell Numbers Are Regulated by WNT and TBX3
title_full_unstemmed Human Breast Progenitor Cell Numbers Are Regulated by WNT and TBX3
title_short Human Breast Progenitor Cell Numbers Are Regulated by WNT and TBX3
title_sort human breast progenitor cell numbers are regulated by wnt and tbx3
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4211891/
https://www.ncbi.nlm.nih.gov/pubmed/25350852
http://dx.doi.org/10.1371/journal.pone.0111442
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