BRCA1 Suppresses Osteopontin-mediated Breast Cancer

Mohamed El-Tanani, Frederick Campbell, Paul Crowe, Pauline Erwin, Paul Harkin, P. Pharoah, B. Ponder, P.S. Rudland

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

BRCA1 is a well described breast cancer susceptibility gene thought to be involved primarily in DNA repair. However, mutation within the BRCA1 transcriptional domain is also implicated in neoplastic transformation of mammary epithelium, but responsible mechanisms are unclear. Here we show in a rat mammary model system that wild type (WT) BRCA1 specifically represses the expression of osteopontin (OPN), a multifunctional estrogen-responsive gene implicated in oncogenic transformation, particularly that of the breast. WT.BRCA1 selectively binds OPN-activating transcription factors estrogen receptor alpha, AP-1, and PEA3, inhibits OPN promoter transactivation, and suppresses OPN mRNA and protein both from an endogenous gene and a relevant model inducible gene. WT.BRCA1 also inhibits OPN-mediated neoplastic transformation characterized by morphology change, anchorage-independent growth, adhesion to fibronectin, and invasion through Matrigel. A mutant BRCA1 allele (Mut.BRCA1) associated with familial breast cancer lacks OPN suppressor effects, binds to WT.BRCA1, and impedes WT.BRCA1 suppression of OPN. Stable transfection of rat breast tumor cell lines with Mut.BRCA1 dramatically up-regulates OPN protein and induces anchorage independent growth. In human primary breast cancer, BRCA1 mutation is significantly associated with OPN overexpression. Taken together, these data suggest that BRCA1 mutation may confer increased tissue-specific cancer risk, in part by disruption of BRCA1 suppression of OPN gene transcription.
Original languageEnglish
Pages (from-to)26587-26601
Number of pages15
JournalJournal of Biological Chemistry
Volume281(36)
Issue number36
DOIs
Publication statusPublished - 08 Sep 2006

Fingerprint

Osteopontin
Breast Neoplasms
Genes
Breast
Mutation
Rats
Alleles
Activating Transcription Factors
Estrogen Receptor alpha
Neoplasm Genes
Transcription Factor AP-1
Transcription
Growth
Tumor Cell Line
Fibronectins
DNA Repair
Transcriptional Activation
Transfection
Tumors
Estrogens

Cite this

El-Tanani, Mohamed ; Campbell, Frederick ; Crowe, Paul ; Erwin, Pauline ; Harkin, Paul ; Pharoah, P. ; Ponder, B. ; Rudland, P.S. / BRCA1 Suppresses Osteopontin-mediated Breast Cancer. In: Journal of Biological Chemistry. 2006 ; Vol. 281(36), No. 36. pp. 26587-26601.
@article{2d87a1d34318430f90e7e5fdd3ab82ec,
title = "BRCA1 Suppresses Osteopontin-mediated Breast Cancer",
abstract = "BRCA1 is a well described breast cancer susceptibility gene thought to be involved primarily in DNA repair. However, mutation within the BRCA1 transcriptional domain is also implicated in neoplastic transformation of mammary epithelium, but responsible mechanisms are unclear. Here we show in a rat mammary model system that wild type (WT) BRCA1 specifically represses the expression of osteopontin (OPN), a multifunctional estrogen-responsive gene implicated in oncogenic transformation, particularly that of the breast. WT.BRCA1 selectively binds OPN-activating transcription factors estrogen receptor alpha, AP-1, and PEA3, inhibits OPN promoter transactivation, and suppresses OPN mRNA and protein both from an endogenous gene and a relevant model inducible gene. WT.BRCA1 also inhibits OPN-mediated neoplastic transformation characterized by morphology change, anchorage-independent growth, adhesion to fibronectin, and invasion through Matrigel. A mutant BRCA1 allele (Mut.BRCA1) associated with familial breast cancer lacks OPN suppressor effects, binds to WT.BRCA1, and impedes WT.BRCA1 suppression of OPN. Stable transfection of rat breast tumor cell lines with Mut.BRCA1 dramatically up-regulates OPN protein and induces anchorage independent growth. In human primary breast cancer, BRCA1 mutation is significantly associated with OPN overexpression. Taken together, these data suggest that BRCA1 mutation may confer increased tissue-specific cancer risk, in part by disruption of BRCA1 suppression of OPN gene transcription.",
author = "Mohamed El-Tanani and Frederick Campbell and Paul Crowe and Pauline Erwin and Paul Harkin and P. Pharoah and B. Ponder and P.S. Rudland",
year = "2006",
month = "9",
day = "8",
doi = "10.1074/jbc.M604403200",
language = "English",
volume = "281(36)",
pages = "26587--26601",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "36",

}

BRCA1 Suppresses Osteopontin-mediated Breast Cancer. / El-Tanani, Mohamed; Campbell, Frederick; Crowe, Paul; Erwin, Pauline; Harkin, Paul; Pharoah, P.; Ponder, B.; Rudland, P.S.

In: Journal of Biological Chemistry, Vol. 281(36), No. 36, 08.09.2006, p. 26587-26601.

Research output: Contribution to journalArticle

TY - JOUR

T1 - BRCA1 Suppresses Osteopontin-mediated Breast Cancer

AU - El-Tanani, Mohamed

AU - Campbell, Frederick

AU - Crowe, Paul

AU - Erwin, Pauline

AU - Harkin, Paul

AU - Pharoah, P.

AU - Ponder, B.

AU - Rudland, P.S.

PY - 2006/9/8

Y1 - 2006/9/8

N2 - BRCA1 is a well described breast cancer susceptibility gene thought to be involved primarily in DNA repair. However, mutation within the BRCA1 transcriptional domain is also implicated in neoplastic transformation of mammary epithelium, but responsible mechanisms are unclear. Here we show in a rat mammary model system that wild type (WT) BRCA1 specifically represses the expression of osteopontin (OPN), a multifunctional estrogen-responsive gene implicated in oncogenic transformation, particularly that of the breast. WT.BRCA1 selectively binds OPN-activating transcription factors estrogen receptor alpha, AP-1, and PEA3, inhibits OPN promoter transactivation, and suppresses OPN mRNA and protein both from an endogenous gene and a relevant model inducible gene. WT.BRCA1 also inhibits OPN-mediated neoplastic transformation characterized by morphology change, anchorage-independent growth, adhesion to fibronectin, and invasion through Matrigel. A mutant BRCA1 allele (Mut.BRCA1) associated with familial breast cancer lacks OPN suppressor effects, binds to WT.BRCA1, and impedes WT.BRCA1 suppression of OPN. Stable transfection of rat breast tumor cell lines with Mut.BRCA1 dramatically up-regulates OPN protein and induces anchorage independent growth. In human primary breast cancer, BRCA1 mutation is significantly associated with OPN overexpression. Taken together, these data suggest that BRCA1 mutation may confer increased tissue-specific cancer risk, in part by disruption of BRCA1 suppression of OPN gene transcription.

AB - BRCA1 is a well described breast cancer susceptibility gene thought to be involved primarily in DNA repair. However, mutation within the BRCA1 transcriptional domain is also implicated in neoplastic transformation of mammary epithelium, but responsible mechanisms are unclear. Here we show in a rat mammary model system that wild type (WT) BRCA1 specifically represses the expression of osteopontin (OPN), a multifunctional estrogen-responsive gene implicated in oncogenic transformation, particularly that of the breast. WT.BRCA1 selectively binds OPN-activating transcription factors estrogen receptor alpha, AP-1, and PEA3, inhibits OPN promoter transactivation, and suppresses OPN mRNA and protein both from an endogenous gene and a relevant model inducible gene. WT.BRCA1 also inhibits OPN-mediated neoplastic transformation characterized by morphology change, anchorage-independent growth, adhesion to fibronectin, and invasion through Matrigel. A mutant BRCA1 allele (Mut.BRCA1) associated with familial breast cancer lacks OPN suppressor effects, binds to WT.BRCA1, and impedes WT.BRCA1 suppression of OPN. Stable transfection of rat breast tumor cell lines with Mut.BRCA1 dramatically up-regulates OPN protein and induces anchorage independent growth. In human primary breast cancer, BRCA1 mutation is significantly associated with OPN overexpression. Taken together, these data suggest that BRCA1 mutation may confer increased tissue-specific cancer risk, in part by disruption of BRCA1 suppression of OPN gene transcription.

UR - http://www.scopus.com/inward/record.url?scp=33748749626&partnerID=8YFLogxK

U2 - 10.1074/jbc.M604403200

DO - 10.1074/jbc.M604403200

M3 - Article

C2 - 16807234

VL - 281(36)

SP - 26587

EP - 26601

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 36

ER -