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Insulin-Like Growth Factor-I Activates Gene Transcription Programs Strongly Associated With Poor Breast Cancer Prognosis

Chad J. Creighton, Angelo Casa, ZaWaunyka Lazard, Shixia Huang, Anna Tsimelzon, Susan G. Hilsenbeck, Charles Kent Osborne, Adrian V. Lee

From the Breast Center, Departments of Medicine and Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Division of Biostatistics, Baylor College of Medicine, Houston, TX

Corresponding author: Adrian V. Lee, PhD, Breast Center, Baylor College of Medicine, One Baylor Plaza, MS 600; Room N1110, Houston, TX 77030; e-mail: avlee{at}bcm.tmc.edu

Purpose Substantial evidence implicates insulin-like growth factor-I (IGF-I) signaling in the development and progression of breast cancer. To more clearly elucidate the role of IGF in human breast cancer, we identified and then examined gene expression patterns of IGF-I–treated breast cancer cells.

Methods MCF-7 cells were stimulated with IGF-I for 3 or 24 hours and were profiled for greater than 22,000 RNA transcripts. We defined an IGF-I signature pattern of more than 800 genes that were up- or downregulated at both time points. The gene signature was examined in clinical breast tumors and in experimental models that represented other oncogenic pathways. The signature was correlated with clinical and pathologic variables and with patient outcome.

Results IGF-I caused temporal changes in gene expression that were strongly associated with cell proliferation, metabolism, and DNA repair. Genes with early and sustained regulation by IGF-I were highly enriched for transcriptional targets of the estrogen receptor (ER), Ras/extracellular signal-related kinase 1/2, and phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathways. In three large, independent data sets of profiled human breast tumors, the IGF-I signature was manifested in the majority of ER-negative breast tumors and in a subset (approximately 25%) of ER-positive breast tumors. Patients who had tumors that manifested the IGF-I signature (including patients who did not receive adjuvant therapy) had a shorter time to a poor outcome event. The IGF gene signature was highly correlated with numerous poor prognostic factors and was one of the strongest indicators of disease outcome.

Conclusion Transcriptional targets of IGF-I represent pathways of increased aggressiveness and possibly hormone independence in clinical breast cancers.

Supported in part by National Institutes of Health Grants No. P01CA30195 (A.V.L.), P30CA125123 (C.K.O.), and P50CA58183 (C.K.O.) and by a research grant from the Baylor College of Medicine/AstraZeneca Alliance (A.V.L.).

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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