Article

Intratumoral IGF-I protein expression is selectively upregulated in breast cancer patients with BRCA1/2 mutations.

Clinical Division of Special Gynecology, Department of Gynecology and Obstetrics, Medical University of Vienna, and Otto Wagner Hospital, Vienna, Austria.
Endocrine Related Cancer (impact factor: 4.36). 01/2008; 14(4):1053-62. DOI:10.1677/ERC-06-0075 pp.1053-62
Source: PubMed

ABSTRACT BRCA1/2 mutations predispose to early onset breast and ovarian cancers. The phenotypic expression of mutant alleles, however, is thought to be modified by factors that are also involved in the pathogenesis of sporadic breast cancer. One such protein is IGF-I, one of the strongest mitogens to breast cancer cells in vitro. We have utilized immunohistochemistry to compare the intratumoral IGF-I and IGF-I receptor (IGF-IR) protein expression in 57 BRCA1/2 mutation carriers and 102 matched breast cancer patients without a family history in a nested case-control study. BRCA1 silencing by siRNA was used to investigate the effect of BRCA mutations on IGF-I protein expression. IGF-I protein expression was detected in tumoral epithelium and surrounding stroma, and was significantly upregulated in tumors of BRCA mutation carriers when compared with matched sporadic tumors (epithelial: 87.7% vs 61.8%, P=0.001; stromal: 73.7% vs 34.3%, P<0.001). By contrast, IGF-IR protein expression was confined to malignant epithelium and was unchanged in mutation carriers (52.6% vs 39.2%, P=0.310). While in mutation carriers IGF-IR protein expression was significantly correlated with both epithelial (P=0.003) and stromal IGF-I (P=0.02), this association was less pronounced in sporadic breast cancer (P=0.02 respectively). siRNA-mediated downregulation of BRCA1 in primary human mammary gland cells triggered upregulation of endogenous intracellular IGF-I in vitro. The increased intratumoral IGF-I protein expression in BRCA mutation carriers suggests an involvement of the IGF-I/IGF-IR axis in the biological behavior of breast cancers in this population and could define a potential therapeutic target.

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Keywords

57 BRCA1/2 mutation carriers
 
BRCA mutation carriers
 
BRCA mutations
 
BRCA1/2 mutations predispose
 
breast cancer cells
 
breast cancer patients
 
breast cancers
 
endogenous intracellular IGF-I
 
IGF-I protein expression
 
IGF-I/IGF-IR axis
 
IGF-IR protein expression
 
increased intratumoral IGF-I protein expression
 
mutation carriers IGF-IR protein expression
 
nested case-control study
 
onset breast
 
ovarian cancers
 
phenotypic expression
 
potential therapeutic target
 
siRNA-mediated downregulation
 
sporadic breast cancer