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

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%, PZ0.001; 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%, PZ0.310). While in mutation carriers IGF-IR protein expression was significantly correlated with both epithelial (PZ0.003) and stromal IGF-I (PZ0.02), this association was less pronounced in sporadic breast cancer (PZ0.02 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.

Local Expression of Insulin-Like Growth Factor-I, Insulin-Like Growth Factor-I Receptor, and Estrogen Receptor Alpha in Ovarian Cancer

“…[26]in1991dem-onstrated mRNA for IGF-I in 3 of 10 human ovarian cell lines and in 7 of 7 primary and metastatic ovarian cancer surgicalspecimensbyRNaseprotectionassay.Thecelllines and surgical specimens predominantly expressed an IGF-I mRNAtranscriptwithanalternatefirstexon.Inagroupof patientswithinvasiveovariancancers,IGF-Ilevelsinfluids obtainedfromtumorsweresignificantlymoreelevatedthan influidsfrombenigncystsorborderlinetumors [7].Similar resultshavebeenfound,notonlyinovariancancer,butalso in other malignant disease [27,[29][30][31]. IGF-I gene expressionwasincreasedincolorectalcancerwhencomparedwith adjacentnormalmucosa [27],andthelocaleffectsofIGF-I are important in colorectal tumorigenesis and tumor neovascularization [28].…”

“…IGF-I gene expressionwasincreasedincolorectalcancerwhencomparedwith adjacentnormalmucosa [27],andthelocaleffectsofIGF-I are important in colorectal tumorigenesis and tumor neovascularization [28]. High levels of IGF-I expression were alsofoundinbreastcancer [29],glioma [30],andpancreatic cancer [31].…”

Functional variant of KLOTHO: a breast cancer risk modifier among BRCA1 mutation carriers of Ashkenazi origin

“…In addition, intact BRCA1 protein can lower IGF-1 receptor levels in breast cancer cells (Hudelist et al, 2007;Maor et al, 2007). Klotho-V allele shows reduced excretion and enzymatic activity (Figure 2b; Arking et al, 2002).…”

Combination therapy approaches to target insulin-like growth factor receptor signaling in breast cancer

“…IGF1R and DNA-damaging agents BRCA-mutated breast cancers are susceptible to the impairment of DNA damage repair by homologous recombination and interestingly are known to have high IGF-1 protein expression (Hudelist et al 2007). Specific therapies aimed at targeting DNA repair factors include poly ADPribose polymerase (PARP) inhibitors (e.g.…”