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

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

Research output: Contribution to journalArticle

840 Citations (Scopus)

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 .

Original languageEnglish (US)
Pages (from-to)907-913
Number of pages7
JournalNature medicine
Volume15
Issue number8
DOIs
StatePublished - Aug 1 2009
Externally publishedYes

Fingerprint

Health Services Needs and Demand
Tumors
Tissue
Breast
Stem Cells
Mutation
Stem cells
Neoplasms
Tumor Suppressor Proteins
Gene encoding
Breast Neoplasms
Population
BRCA1 Gene
Receptor Protein-Tyrosine Kinases
Ports and harbors
Gene expression
Gene Expression Profiling
Intercellular Signaling Peptides and Proteins

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Lim, E., Vaillant, F., Wu, D., Forrest, N. C., Pal, B., Hart, A. H., ... Lindeman, G. J. (2009). Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nature medicine, 15(8), 907-913. https://doi.org/10.1038/nm.2000

Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. / Lim, Elgene; Vaillant, François; Wu, Di; Forrest, Natasha C.; Pal, Bhupinder; Hart, Adam H.; Labat, Marie-Liesse; Gyorki, David E.; Ward, Teresa; Partanen, Audrey; Feleppa, Frank; Huschtscha, Lily I.; Thorne, Heather J.; Fox, Stephen B.; Yan, Max; French, Juliet D.; Brown, Melissa A.; Smyth, Gordon K.; Visvader, Jane E.; Lindeman, Geoffrey J.

In: Nature medicine, Vol. 15, No. 8, 01.08.2009, p. 907-913.

Research output: Contribution to journalArticle

Lim, E, Vaillant, F, Wu, D, Forrest, NC, Pal, B, Hart, AH, Labat, M-L, 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 2009, 'Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers', Nature medicine, vol. 15, no. 8, pp. 907-913. https://doi.org/10.1038/nm.2000
Lim, Elgene ; Vaillant, François ; Wu, Di ; Forrest, Natasha C. ; Pal, Bhupinder ; Hart, Adam H. ; Labat, Marie-Liesse ; Gyorki, David E. ; Ward, Teresa ; Partanen, Audrey ; Feleppa, Frank ; Huschtscha, Lily I. ; Thorne, Heather J. ; Fox, Stephen B. ; Yan, Max ; French, Juliet D. ; Brown, Melissa A. ; Smyth, Gordon K. ; Visvader, Jane E. ; Lindeman, Geoffrey J. / Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. In: Nature medicine. 2009 ; Vol. 15, No. 8. pp. 907-913.
@article{f7e9150cca424b499bff93d75e094ba4,
title = "Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers",
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 .",
author = "Elgene Lim and Fran{\cc}ois Vaillant and Di Wu and Forrest, {Natasha C.} and Bhupinder Pal and Hart, {Adam H.} and Marie-Liesse Labat and Gyorki, {David E.} and Teresa Ward and Audrey Partanen and Frank Feleppa and Huschtscha, {Lily I.} and Thorne, {Heather J.} and Fox, {Stephen B.} and Max Yan and French, {Juliet D.} and Brown, {Melissa A.} and Smyth, {Gordon K.} and Visvader, {Jane E.} and Lindeman, {Geoffrey J.}",
year = "2009",
month = "8",
day = "1",
doi = "10.1038/nm.2000",
language = "English (US)",
volume = "15",
pages = "907--913",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "8",

}

TY - JOUR

T1 - Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers

AU - Lim, Elgene

AU - Vaillant, François

AU - Wu, Di

AU - Forrest, Natasha C.

AU - Pal, Bhupinder

AU - Hart, Adam H.

AU - Labat, Marie-Liesse

AU - Gyorki, David E.

AU - Ward, Teresa

AU - Partanen, Audrey

AU - Feleppa, Frank

AU - Huschtscha, Lily I.

AU - Thorne, Heather J.

AU - Fox, Stephen B.

AU - Yan, Max

AU - French, Juliet D.

AU - Brown, Melissa A.

AU - Smyth, Gordon K.

AU - Visvader, Jane E.

AU - Lindeman, Geoffrey J.

PY - 2009/8/1

Y1 - 2009/8/1

N2 - 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 .

AB - 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 .

UR - http://www.scopus.com/inward/record.url?scp=68349130357&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=68349130357&partnerID=8YFLogxK

U2 - 10.1038/nm.2000

DO - 10.1038/nm.2000

M3 - Article

VL - 15

SP - 907

EP - 913

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

IS - 8

ER -