IGF-II plays a critical role in normal mammary gland development, and also regulates proliferation, survival and metastasis of breast cancer cells by signaling through the IGF-IR, Insulin receptors and activating the estrogen signaling cascade. Although IGF-II is not expressed in normal adult cells, it is re-expressed in breast cancer (predominantly as precursor IGF-II or proIGF-II), and “free” circulating IGF-II levels correlate to breast tumor size. Furthermore, the higher incidence of breast cancer in Caucasian women relative to the higher mortality observed among AA women prompted us to focus our present study on: 1) Comparing IGF-II [mature (mIGF-II) and proIGF-II] expression between AA and Caucasian cell lines and paired (normal/tumor)breast tissue samples; 2) Activation of intracellular signaling pathways by mIGF-II and proIGF-II; and 3) MIGF-II and proIGF-II effects on the anti-apoptotic proteins Bcl-2, Bcl-XL and Survivin expression in AA and Caucasian cell lines. Our results showed significantly higher levels of proIGF-II in the AA breast cancer cell line CRL-2329 than in the MCF-7 Caucasian breast cancer cells. Furthermore, proIGF-II was more potent than mIGF-II in activating the PI3K/Akt pathway and stimulating Bcl-2, Bcl-XL and survivin expression in CRL-2329 and MCF-7 cells, while transfection with IGF-II SiRNA significantly decreased the anti-apoptotic proteins expression. Of great significance was the higher expression of these proteins detected in normal tissue from AA women as compared to Caucasian women. Thus, we propose that cancer initiated by these cells may promote the development of a more aggressive, malignant tumor contributing to the increased mortality observed among AA breast cancer patients. We conclude that IGF-II effects in the mitochondria and its regulation of survival proteins is a novel mechanism of cancer cell survival and chemoresistance.
99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA