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Insulin-like growth factor regulation of mammary gland development and tumorigenesis

Insulin-like growth factors (IGFs) are potent mitogens and survival factors. In the mammary gland, IGFs stimulate proliferation, differentiation, and survival during numerous developmental stages; IGF signaling is required for puberty-dependent ductal outgrowth, stimulates lobuloalveolar development during pregnancy, and is reduced or absent during apoptosis-driven involution. Much of our knowledge of IGF action in the mammary gland in vivo comes from knockout or transgenic models. However, very few of these studies have examined the consequence of these gene alterations on IGF signaling in vivo. We have recently shown that intravenous injection of IGF-I stimulates IGF-IR and IRS phosphorylation in the mammary gland, and we are currently assessing the effect of targeted gene deletion of overexpression of IGF signaling components on downstream signaling in the mammary gland in vivo.

Many years of research have shown that the proliferative and survival functions of the IGFs are not only important in mammary gland development, but are also strongly involved in mammary cancer. Early work using breast cancer cell lines in vitro showed that IGFs could increase cell growth and survival; in particular, that IGFs could block the effects of chemotherapy. We have recently shown that breast cancer cell lines grown as xenografts in vivo are also sensitive to intravenous IGF stimulation, and several IGF-IR inhibitors have been shown in the past year to block MCF-7 xenograft growth.

IGF-IR and its downstream signaling intermediate IRS-1 can transform fibroblasts in vitro. To date there is no evidence for their transforming ability in vivo using transgenic mice. We have recently characterized mice that overexpress IGF-IR, IRS-1, or IRS-2 in the mammary gland, using mouse mammary tumor virus directed overexpression. We have found that overexpression of a constitutively active IGF-IR in the mammary gland disrupts normal development, such that female mice are unable to lactate, and that mice rapidly develop mammary tumors. Interestingly, overexpression of IRS-1 or IRS-2 also causes mammary tumorigenesis, albeit with a longer time to tumor formation than dominant active IGF-IR. These are the first mouse models showing that IGF-IR or IRS overexpression leads to tumorigenesis in vivo. We are currently examining the pathways required for IGF-IR and IRS-mediated tumorigenesis in the mammary gland.

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Lee, A. Insulin-like growth factor regulation of mammary gland development and tumorigenesis. Breast Cancer Res 7 (Suppl 2), S.23 (2005).

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