Journal Article

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

Lim, Elgene, Gyorki, David E, Partanen, Audrey, Visvader, Jane E, Pal, Bhupinder, Fox, Stephen B, Forrest, Natasha C, French, Juliet D, Wu, Di, Hart, Adam H, Ward, Teresa, Feleppa, Frank, Smyth, Gordon K, Huschtscha, Lily I, Asselin-Labat, Marie-Liesse, Brown, Melissa A, Vaillant, François, Lindeman, Geoffrey J, Thorne, Heather J, Yan, Max

2009

Overview

Contrary to the belief that basal-like breast cancers develop from mammary stem cells in BRCA1 mutation carriers, an aberrant luminal progenitor population might be the target for transformation in basal tumors in these individuals ( pages 842–844 ). 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 US,Nature Publishing Group
• Subject: Biomedical and Life Sciences / Biomedicine / BRCA mutations / Breast cancer / Breast Neoplasms - etiology / Breast Neoplasms - genetics / Cancer Research / Cell Transformation, Neoplastic - genetics / Cells, Cultured / Cellular biology / Female / Gene expression / Gene Expression Profiling / Gene Expression Regulation, Neoplastic / Genes, BRCA1 / Genetic aspects / Health aspects / Heterozygote / Humans / Infectious Diseases / Mammary Glands, Human - cytology / Mammary Glands, Human - metabolism / Mammary Glands, Human - pathology / Metabolic Diseases / Models, Biological / Molecular Medicine / Mutation / Mutation - physiology / Neoplastic Stem Cells - metabolism / Neoplastic Stem Cells - pathology / Neurosciences / Physiological aspects / Precancerous Conditions - genetics / Precancerous Conditions - metabolism / Precancerous Conditions - pathology / Receptors, Progesterone - metabolism / Risk factors / Stem cells / Stem Cells - metabolism / Stem Cells - pathology / Subpopulations / Tissues / Tumor suppressor genes / Tumors