Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers

Lim, E; Vaillant, F; Wu, D; Forrest, NC; Pal, B; Hart, AH; Asselin-Labat, ML; Gyorki, DE; Ward, T; Partanen, A; Feleppa, F; Huschtscha, LI; Thorne, HJ; Fox, SB; Yan, M; French, JD; Brown, MA; Smyth, GK; Visvader, JE; Lindeman, GJ

Author(s): Lim, E; Vaillant, F; Wu, D; Forrest, NC; Pal, B; Hart, AH; Asselin-Labat, ML; Gyorki, DE; Ward, T; Partanen, A; Feleppa, F; Huschtscha, LI; Thorne, HJ; Fox, SB; Yan, M; French, JD; Brown, MA; Smyth, GK; Visvader, JE; Lindeman, GJ;
Details: Publication Year 2009-08,Volume 15,Issue #8,Page 907-913
Journal Title: NATURE MEDICINE
Publication Type: Journal Article
Abstract: Basal-like breast cancers arising in women carrying mutations in the BRCA1 gene, encoding the tumor suppressor protein BRCA1, are thought to develop from the mammary stem cell. To explore early cellular changes that occur in BRCA1 mutation carriers, we have prospectively isolated distinct epithelial subpopulations from normal mammary tissue and preneoplastic specimens from individuals heterozygous for a BRCA1 mutation. We describe three epithelial subsets including basal stem/progenitor, luminal progenitor and mature luminal cells. Unexpectedly, we found that breast tissue from BRCA1 mutation carriers harbors an expanded luminal progenitor population that shows factor-independent growth in vitro. Moreover, gene expression profiling revealed that breast tissue heterozygous for a BRCA1 mutation and basal breast tumors were more similar to normal luminal progenitor cells than any other subset, including the stem cell-enriched population. The c-KIT tyrosine kinase receptor (encoded by KIT) emerged as a key marker of luminal progenitor cells and was more highly expressed in BRCA1-associated preneoplastic tissue and tumors. Our findings suggest that an aberrant luminal progenitor population is a target for transformation in BRCA1-associated basal tumors.
Publisher: NATURE PUBLISHING GROUP
Keywords: MAMMARY EPITHELIAL-CELLS; REDUCING SALPINGO-OOPHORECTOMY; HUMAN BREAST-TUMORS; ADULT HUMAN BREAST; STEM-CELLS; CANCER SUSCEPTIBILITY; MICE; DIFFERENTIATION; GLAND; RISK
Publisher's Version: https://doi.org/10.1038/nm.2000
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2009-08-01 12:00:00