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Mammary stem cells and progenitors: targeting the roots of breast cancer for prevention.

ABSTRACT: Breast cancer prevention is daunting, yet not an unsurmountable goal. Mammary stem and progenitors have been proposed as the cells-of-origin in breast cancer. Here, we present the concept of limiting these breast cancer precursors as a risk reduction approach in high-risk women. A wealth of information now exists for phenotypic and functional characterization of mammary stem and progenitor cells in mouse and human. Recent work has also revealed the hormonal regulation of stem/progenitor dynamics as well as intrinsic lineage distinctions between mammary epithelial populations. Leveraging these insights, molecular marker-guided chemoprevention is an achievable reality.

SUBMITTER: Tharmapalan P

PROVIDER: S-EPMC6627238 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Mammary stem cells and progenitors: targeting the roots of breast cancer for prevention.

Tharmapalan Pirashaanthy P Mahendralingam Mathepan M Berman Hal K HK Khokha Rama R

The EMBO journal 20190621 14

Breast cancer prevention is daunting, yet not an unsurmountable goal. Mammary stem and progenitors have been proposed as the cells-of-origin in breast cancer. Here, we present the concept of limiting these breast cancer precursors as a risk reduction approach in high-risk women. A wealth of information now exists for phenotypic and functional characterization of mammary stem and progenitor cells in mouse and human. Recent work has also revealed the hormonal regulation of stem/progenitor dynamics ...[more]

PMID: 31267556

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Project description:Triple-negative breast cancer (TNBC) is a heterogeneous group of tumours in which chemotherapy, the current mainstay of systemic treatment, is often initially beneficial but with a high risk of relapse and metastasis. There is currently no means of predicting which TNBC will relapse. We tested the hypothesis that the biological properties of normal stem cells are re-activated in tumour metastasis and that, therefore, the activation of normal mammary stem cell-associated gene sets in primary TNBC would be highly prognostic for relapse and metastasis.Mammary basal stem and myoepithelial cells were isolated by flow cytometry and tested in low-dose transplant assays. Gene expression microarrays were used to establish expression profiles of the stem and myoepithelial populations; these were compared to each other and to our previously established mammary epithelial gene expression profiles. Stem cell genes were classified by Gene Ontology (GO) analysis and the expression of a subset analysed in the stem cell population at single cell resolution. Activation of stem cell genes was interrogated across different breast cancer cohorts and within specific subtypes and tested for clinical prognostic power.A set of 323 genes was identified that was expressed significantly more highly in the purified basal stem cells compared to all other cells of the mammary epithelium. A total of 109 out of 323 genes had been associated with stem cell features in at least one other study in addition to our own, providing further support for their involvement in the biology of this cell type. GO analysis demonstrated an enrichment of these genes for an association with cell migration, cytoskeletal regulation and tissue morphogenesis, consistent with a role in invasion and metastasis. Single cell resolution analysis showed that individual cells co-expressed both epithelial- and mesenchymal-associated genes/proteins. Most strikingly, we demonstrated that strong activity of this stem cell gene set in TNBCs identified those tumours most likely to rapidly progress to metastasis.Our findings support the hypothesis that the biological properties of normal stem cells are drivers of metastasis and that these properties can be used to stratify patients with a highly heterogeneous disease such as TNBC.

Dataset Information

Mammary stem cells and progenitors: targeting the roots of breast cancer for prevention.

Publications

Mammary stem cells and progenitors: targeting the roots of breast cancer for prevention.

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