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Phosphorylated Insulin-Like Growth Factor-I/Insulin Receptor Is Present in All Breast Cancer Subtypes and Is Related to Poor Survival

¹ Laboratory for Oncogenomic Research, Departments of Pediatrics, Experimental Medicine, and Medical Genetics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada; ² Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Cardiff University, Cardiff, Wales, United Kingdom; ³ Bristol-Myers Squibb Oncology Drug Discovery, Princeton, New Jersey; and ⁴ Department of Oncology, Lady Davis Research Institute of the Jewish General Hospital and McGill University, Montreal, Quebec, Canada

Requests for reprints: Sandra E. Dunn, Departments of Pediatrics, Experimental Medicine, and Medical Genetics, Child and Family Research Institute, University of British Columbia, 950 West 28th Avenue, Vancouver, BC, Canada V5Z 4H4. Phone: 604-875-2000, ext. 6015; Fax: 604-875-3120; E-mail: sedunn{at}interchange.ubc.ca.

Key Words: tissue microarray • phospho-IGF-IR • breast cancer • phospho-S6 • BMS-536924

Drugs that target the insulin-like growth factor-I receptor (IGF-IR) and/or insulin receptor (IR) are currently under investigation for a variety of malignancies including breast cancer. Although we have previously reported that IGF-IR expression in primary breast tumors is common, the activation status of this receptor has not been examined in relation to survival. Phosphorylated IGF-IR/IR (P-IGF-IR/IR) and its downstream signaling partner phospho-S6 (P-S6) were evaluated immunohistochemically in tumor tissue microarrays representing 438 cases of invasive breast cancer. P-IGF-IR/IR (n = 114; P = 0.046) and total levels of IR (n = 122; P = 0.009) were indicative of poor survival, whereas total IGF-IR (n = 112; P = 0.304) was not. P-IGF-IR/IR and P-S6 were coordinately expressed in primary breast tumors (likelihood ratio, 11.57; P = 6.70 x 10^–4). Importantly, P-IGF-IR/IR was detected in all breast cancer subtypes (luminal, 48.1%; triple negative, 41.9%; and HER2, 64.3%). In vitro, the IGF-IR/IR inhibitor BMS-536924 decreased phospho-RSK and P-S6, and significantly suppressed the growth of breast cancer cell lines MCF-7, SUM149, and AU565 representing the luminal, triple negative, and HER2 subtypes, respectively, in monolayer and soft agar. BMS-536924 also inhibited growth in tamoxifen resistant MCF-7 Tam-R cells while having little effect on immortalized normal breast epithelial cells. Thus, we can determine which patients have the activated receptor and provide evidence that P-IGF-IR/IR is a prognostic factor for breast cancer. Beyond this, P-IGF-IR/IR could be a predictive marker for response to IGF-IR and/or IR-targeted therapies, as these inhibitors may be of benefit in all breast cancer subtypes including those with acquired resistance to tamoxifen. [Cancer Res 2008;68(24):10238–46]

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