Lowering IGF-I levels for the prevention of breast cancer.

CS23-03

The insulin-like growth factor (IGF) system, and its upstream regulator growth hormone (GH), have both been implicated in the development of breast cancer. Many of the IGF signaling components are oncogenes that can transform mouse fibroblasts (e.g. IGF-IR and IRS-1). Furthermore, both GH and IGF-IR are able to fully transform human immortalized mammary epithelial cells, a feat that is relatively unique and not found with other classical oncogenes such as cyclin D1, ErbB2, or activated ras. Recent transgenic mouse studies showing that both IGF-IR and IRSs can cause mammary tumors confirms their oncogenic potential. IGFs may also act as progression factors in breast cancer, enhancing the propagation of carcinogen-initiated cells. Supporting this, genetic deletion of the liver IGF-I gene in mice impairs carcinogen or oncogene induced tumorigenesis, and loss of GH in rats results in complete resistance to carcinogen-induced mammary carcinogenesis. Correlating with this animal data, humans with high circulating levels of IGF-I (particularly in the context of low levels of IGFBP-3) have increased risk of numerous cancers including pre-menopausal breast cancer. The abundance of laboratory and clinical evidence implicating both GH and IGFs in the development and progression of breast cancer has led to the development of numerous strategies to target these pathways. The IGF system is being targeted at the level of IGF ligands and receptors. IGF-I levels can be lowered by inhibiting GH action, for example with the GH antagonist pegvisomant. This has been shown to block mammary gland development and breast cancer growth. IGF ligands can be neutralized by IGFBPs, and both IGFBP-1 and IGFBP-3 have been shown to block breast cancer growth. IGFs can also be neutralized by antibodies that bind the ligand, and this has been shown to be effective against prostate cancer cells. IGF ligands circulate in nanogram quantities and may be difficult to completely neutralize. Therefore, elimination or blockade of the IGF-IR is being tested for the treatment of breast cancer. The two major clinical strategies include antibodies that block IGF-IR function and cause downregualtion and elimination of the receptor, and small molecule inhibitors that block the tyrosine kinase domain of IGF-IR. Both strategies have shown success in preclinical models of breast cancer. Given the preclinical and clinical evidence implicating the IGF system in breast cancer progression, and evidence that IGF levels predicts breast cancer risk, strategies to inhibit IGF action should be tested for risk reduction or prevention of breast cancer. Potential toxicities resulting from loss of GH or IGF action will need to be considered and factored into any program.