Phosphorylated insulin-like growth factor-I/insulin receptor is present in all breast cancer subtypes and is related to poor survival

Law, Jennifer H., Habibi, Golareh, Hu, Kaiji, Masoudi, Hamid, Wang, Michelle. Y. C., Stratford, Anna L., Park, Eugene, Gee, Julia Margaret Wendy ORCID: https://orcid.org/0000-0001-6483-2015, Finlay, Pauline, Jones, Helen E., Nicholson, Robert Ian, Carboni, Joan, Gottardis, Marco, Pollak, Michael and Dunn, Sandra E. 2008. Phosphorylated insulin-like growth factor-I/insulin receptor is present in all breast cancer subtypes and is related to poor survival. Cancer Research 68 (24) , pp. 10238-10246. 10.1158/0008-5472.CAN-08-2755

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Abstract

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 × 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]

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences Pharmacy
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) R Medicine > RM Therapeutics. Pharmacology
Uncontrolled Keywords:	tissue microarray; phospho-IGF-IR; breast cancer; phospho-S6; BMS-536924
Publisher:	American Association for Cancer Research
ISSN:	0008-5472
Last Modified:	18 Oct 2022 14:18
URI:	https://orca.cardiff.ac.uk/id/eprint/17109

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