for those her2s who are BRCA1/2 psotive, a possible new target

[Lani]

Endocr Relat Cancer. 2007 Dec;14(4):1053-1062.
Intratumoral IGF-I protein expression is selectively upregulated in breast cancer patients with BRCA1/2 mutations.

Hudelist G, Wagner T, Rosner M, Fink-Retter A, Gschwantler-Kaulich D, Czerwenka K, Kroiss R, Tea M, Pischinger K, Köstler WJ, Attems J, Mueller R, Blaukopf C, Kubista E, Hengstschläger M, Singer CF.
Clinical Division of Special Gynecology and Division of Medical Genetics, Department of Gynecology and Obstetrics, Medical University of Vienna, Vienna, A-1090, Austria Department of Obstetrics and Gynecology, LKH Villach, Villach, Austria Division of Gynecopathology, Department of Pathology and Clinical Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria Institute of Pathology, Otto Wagner Hospital, Vienna, Austria Ludwig Boltzmann Society for Clinical and Experimental Oncology, Vienna, A-1090, Austria.
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.
PMID: 18045956 [PubMed - as supplied by publisher]