Cargando…
BRCA1 mutation influences progesterone response in human benign mammary organoids
BACKGROUND: Women, who carry a germline BRCA1 gene mutation, have a markedly increased risk of developing breast cancer during their lifetime. While BRCA1 carriers frequently develop triple-negative, basal-like, aggressive breast tumors, hormone signaling is important in the genesis of BRCA1 mutant...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878650/ https://www.ncbi.nlm.nih.gov/pubmed/31771627 http://dx.doi.org/10.1186/s13058-019-1214-0 |
_version_ | 1783473491823034368 |
---|---|
author | Davaadelger, Batzaya Choi, Mi-Ran Singhal, Hari Clare, Susan E. Khan, Seema A. Kim, J. Julie |
author_facet | Davaadelger, Batzaya Choi, Mi-Ran Singhal, Hari Clare, Susan E. Khan, Seema A. Kim, J. Julie |
author_sort | Davaadelger, Batzaya |
collection | PubMed |
description | BACKGROUND: Women, who carry a germline BRCA1 gene mutation, have a markedly increased risk of developing breast cancer during their lifetime. While BRCA1 carriers frequently develop triple-negative, basal-like, aggressive breast tumors, hormone signaling is important in the genesis of BRCA1 mutant breast cancers. We investigated the hormone response in BRCA1-mutated benign breast tissue using an in vitro organoid system. METHODS: Scaffold-free, multicellular human breast organoids generated from benign breast tissues from non-carrier or BRCA1 mutation carriers were treated in vitro with a stepwise menstrual cycle hormone regimen of estradiol (E2) and progesterone (P4) over the course of 28 days. RESULTS: Breast organoids exhibited characteristics of the native breast tissue, including expression of hormone receptors, collagen production, and markers of luminal and basal epithelium, and stromal fibroblasts. RNA sequencing analysis revealed distinct gene expression in response to hormone treatment in the non-carrier and BRCA1-mutated organoids. The selective progesterone receptor modulator, telapristone acetate (TPA), was used to identify specifically PR regulated genes. Specifically, extracellular matrix organization genes were regulated by E2+P4+TPA in the BRCA1-mutated organoids but not in the non-carrier organoids. In contrast, in the non-carrier organoids, known PR target genes such as the cell cycle genes were inhibited by TPA. CONCLUSIONS: These data show that BRCA1 mutation influences hormone response and in particular PR activity which differs from that of non-carrier organoids. Our organoid model system revealed important insights into the role of PR in BRCA1-mutated benign breast cells and the critical paracrine actions that modify hormone receptor (HR)-negative cells. Further analysis of the molecular mechanism of BRCA1 and PR crosstalk is warranted using this model system. |
format | Online Article Text |
id | pubmed-6878650 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-68786502019-11-29 BRCA1 mutation influences progesterone response in human benign mammary organoids Davaadelger, Batzaya Choi, Mi-Ran Singhal, Hari Clare, Susan E. Khan, Seema A. Kim, J. Julie Breast Cancer Res Research Article BACKGROUND: Women, who carry a germline BRCA1 gene mutation, have a markedly increased risk of developing breast cancer during their lifetime. While BRCA1 carriers frequently develop triple-negative, basal-like, aggressive breast tumors, hormone signaling is important in the genesis of BRCA1 mutant breast cancers. We investigated the hormone response in BRCA1-mutated benign breast tissue using an in vitro organoid system. METHODS: Scaffold-free, multicellular human breast organoids generated from benign breast tissues from non-carrier or BRCA1 mutation carriers were treated in vitro with a stepwise menstrual cycle hormone regimen of estradiol (E2) and progesterone (P4) over the course of 28 days. RESULTS: Breast organoids exhibited characteristics of the native breast tissue, including expression of hormone receptors, collagen production, and markers of luminal and basal epithelium, and stromal fibroblasts. RNA sequencing analysis revealed distinct gene expression in response to hormone treatment in the non-carrier and BRCA1-mutated organoids. The selective progesterone receptor modulator, telapristone acetate (TPA), was used to identify specifically PR regulated genes. Specifically, extracellular matrix organization genes were regulated by E2+P4+TPA in the BRCA1-mutated organoids but not in the non-carrier organoids. In contrast, in the non-carrier organoids, known PR target genes such as the cell cycle genes were inhibited by TPA. CONCLUSIONS: These data show that BRCA1 mutation influences hormone response and in particular PR activity which differs from that of non-carrier organoids. Our organoid model system revealed important insights into the role of PR in BRCA1-mutated benign breast cells and the critical paracrine actions that modify hormone receptor (HR)-negative cells. Further analysis of the molecular mechanism of BRCA1 and PR crosstalk is warranted using this model system. BioMed Central 2019-11-26 2019 /pmc/articles/PMC6878650/ /pubmed/31771627 http://dx.doi.org/10.1186/s13058-019-1214-0 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Davaadelger, Batzaya Choi, Mi-Ran Singhal, Hari Clare, Susan E. Khan, Seema A. Kim, J. Julie BRCA1 mutation influences progesterone response in human benign mammary organoids |
title | BRCA1 mutation influences progesterone response in human benign mammary organoids |
title_full | BRCA1 mutation influences progesterone response in human benign mammary organoids |
title_fullStr | BRCA1 mutation influences progesterone response in human benign mammary organoids |
title_full_unstemmed | BRCA1 mutation influences progesterone response in human benign mammary organoids |
title_short | BRCA1 mutation influences progesterone response in human benign mammary organoids |
title_sort | brca1 mutation influences progesterone response in human benign mammary organoids |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878650/ https://www.ncbi.nlm.nih.gov/pubmed/31771627 http://dx.doi.org/10.1186/s13058-019-1214-0 |
work_keys_str_mv | AT davaadelgerbatzaya brca1mutationinfluencesprogesteroneresponseinhumanbenignmammaryorganoids AT choimiran brca1mutationinfluencesprogesteroneresponseinhumanbenignmammaryorganoids AT singhalhari brca1mutationinfluencesprogesteroneresponseinhumanbenignmammaryorganoids AT claresusane brca1mutationinfluencesprogesteroneresponseinhumanbenignmammaryorganoids AT khanseemaa brca1mutationinfluencesprogesteroneresponseinhumanbenignmammaryorganoids AT kimjjulie brca1mutationinfluencesprogesteroneresponseinhumanbenignmammaryorganoids |