Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers.
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 .
Lim
Elgene
E
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Vaillant
François
F
Wu
Di
D
Forrest
Natasha C
NC
Pal
Bhupinder
B
Hart
Adam H
AH
Asselin-Labat
Marie-Liesse
ML
Gyorki
David E
DE
Ward
Teresa
T
Partanen
Audrey
A
Feleppa
Frank
F
Huschtscha
Lily I
LI
Thorne
Heather J
HJ
Fox
Stephen B
SB
Yan
Max
M
French
Juliet D
JD
Brown
Melissa A
MA
Smyth
Gordon K
GK
Visvader
Jane E
JE
Lindeman
Geoffrey J
GJ
D001943:Breast Neoplasms / Q000209:etiology / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D019398:Genes, BRCA1; D006579:Heterozygote; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D008954:Models, Biological; D009154:Mutation / Q000502:physiology; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011980:Receptors, Progesterone / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology*
D011980:Receptors, Progesterone