Prolactin receptor-driven combined luminal and epithelial differentiation in breast cancer restricts plasticity, stemness, tumorigenesis and metastasis.

Journal

Oncogenesis
ISSN: 2157-9024
Titre abrégé: Oncogenesis
Pays: United States
ID NLM: 101580004

Informations de publication

Date de publication:
14 Jan 2021
Historique:
received: 27 07 2020
accepted: 11 12 2020
revised: 09 12 2020
entrez: 15 1 2021
pubmed: 16 1 2021
medline: 16 1 2021
Statut: epublish

Résumé

Dedifferentiation increased cellular plasticity and stemness are established derivers of tumor heterogeneity, metastasis and therapeutic failure resulting in incurable cancers. Therefore, it is essential to decipher pro/forward-differentiation mechanisms in cancer that may serve as therapeutic targets. We found that interfering with expression of the receptor for the lactogenic hormone prolactin (PRLR) in breast cancer cells representative of the luminal and epithelial breast cancer subtypes (hormone receptor positive (HR+) and HER2-enriched (HER2-E) resulted in loss of their differentiation state, enriched for stem-like cell subpopulations, and increased their tumorigenic capacity in a subtype-specific manner. Loss of PRLR expression in HR+ breast cancer cells caused their dedifferentiation generating a mesenchymal-basal-like phenotype enriched in CD44+ breast cancer stem-like cells (BCSCs) showing high tumorigenic and metastatic capacities and resistance to anti-hormonal therapy. Whereas loss of PRLR expression in HER2-E breast cancer cells resulted in loss of their luminal differentiation yet enriched for epithelial ALDH+ BCSC population showing elevated HER2-driven tumorigenic, multi-organ metastatic spread, and resistance to anti-HER2 therapy. Collectively, this study defines PRLR as a driver of precise luminal and epithelial differentiation limiting cellular plasticity, stemness, and tumorigenesis and emphasizing the function of pro/forward-differentiation pathways as a foundation for the discovery of anti-cancer therapeutic targets.

Identifiants

DOI: 10.1038/s41389-020-00297-5 PMID: 33446633 PMC: PMC7809050
pubmed: 33446633
doi: 10.1038/s41389-020-00297-5
pii: 10.1038/s41389-020-00297-5
pmc: PMC7809050
doi:

Types de publication

Journal Article

Langues

eng

Pagination

10

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Auteurs

Anwar Shams (A)

Department of Medicine, Cancer Research Program, The Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
Department of Pharmacology, Faculty of Medicine, Taif University, Taif, Saudi Arabia.

Najat Binothman (N)

Department of Medicine, Cancer Research Program, The Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
Department of Chemistry, College of Science and Arts, King Abdulaziz University, P.O. Box 344, Rabigh, 21911, Saudi Arabia.

Julien Boudreault (J)

Department of Medicine, Cancer Research Program, The Research Institute of the McGill University Health Centre, Montreal, QC, Canada.

Ni Wang (N)

Department of Medicine, Cancer Research Program, The Research Institute of the McGill University Health Centre, Montreal, QC, Canada.

Fuad Shams (F)

Department of Pathology and Laboratory Medicine, King Abdulaziz Hospital, Mecca, Saudi Arabia.

Dana Hamam (D)

Department of Medicine, Cancer Research Program, The Research Institute of the McGill University Health Centre, Montreal, QC, Canada.

Jun Tian (J)

Department of Medicine, Cancer Research Program, The Research Institute of the McGill University Health Centre, Montreal, QC, Canada.

Alaa Moamer (A)

Department of Medicine, Cancer Research Program, The Research Institute of the McGill University Health Centre, Montreal, QC, Canada.

Meiou Dai (M)

Department of Medicine, Cancer Research Program, The Research Institute of the McGill University Health Centre, Montreal, QC, Canada.

Jean-Jacques Lebrun (JJ)

Department of Medicine, Cancer Research Program, The Research Institute of the McGill University Health Centre, Montreal, QC, Canada.

Suhad Ali (S)

Department of Medicine, Cancer Research Program, The Research Institute of the McGill University Health Centre, Montreal, QC, Canada. suhad.ali@mcgill.ca.
ORCID: 0000-0002-9027-6232

Classifications MeSH