The IGF System in Mammary Development and Breast Cancer

Abstract

The IGFs, receptors and binding proteins have emerged as critical mediators in growth of mammary/breast epithelium both in normal developmental processes and in tumorigenesis. The function of this system in mammary development and breast cancer was first reviewed in this journal in 2000. At that time, an essential role for IGF-I in pubertal mammary growth and for the IGF-IR in TEB proliferation and ductal outgrowth in mice had just been established [1–3]. It was also recently clear that the IGF ligands were expressed locally in the gland in both epithelial and stromal locations [4, 5] raising the question of how circulating and local IGFs mediate epithelial growth. Local overexpression of the ligands primarily demonstrated that the IGFs were potent survival factors for mammary epithelial cells and could inhibit apoptosis during involution [6, 7]. A role for the IGF binding proteins, IGFBP-5 in particular, also was proposed in the apoptotic events of involution in part by inhibiting IGF actions as well as by IGFindependent functions [8, 9]. In breast cancer, the IGFs, IGFBPs and IGF-IR were an intense focus due to their proposed link with breast cancer susceptibility, role in breast tumor cell biology and interaction with estrogen receptor (ER) signaling. While these data were intriguing, there were no therapeutic strategies designed to test the function of IGF signaling in human subjects. With the clear demonstration that targeting growth factor receptor signaling in cancer has value (epidermal growth factor receptor, vascular endothelial growth factor receptor, etc.), the therapeutic field has changed dramatically. The reviews on IGF biology in mammary development and neoplasia in the 2000 reviews proposed hypotheses and raised a number of critical unanswered questions. Eight years later, we now have the opportunity in the current issue to revisit the IGF system in mammary development and breast cancer and to determine whether investigations during the intervening period answered any of these questions and led to revised hypotheses. Two major issues that were raised in the prior issue concerning IGF and IGFBP function in mammary/breast tissue were how these molecules are involved in hormone-mediated growth of epithelial cells and their role as endocrine versus autocrine/ paracrine growth factors. It is of note that a number of the updated reviews in this issue address these same questions both from the perspective of normal growth and developmental processes and of susceptibility and growth of breast cancers. New data presented here have led to a greater understanding of these questions but have not yet provided complete answers. While it was previously established that IGF-I is a local mediator of GH actions in mammary development, Kleinberg and Ruan review the increasingly complex roles for IGFs in both estrogen and progesterone events in mammary epithelial growth in rodents. Rowzee et al review new studies suggesting distinct roles for IGF-I expressed in epithelial and stromal compartments in the context of IGF-I as an endocrine or autocrine/paracrine mediator of growth. They also discuss the increasing evidence that IGF-I and IGF-II are independently regulated and have unique functions during postnatal mammary development. Endocrine IGF function is also the focus of the Lann and LeRoith review in the context of breast cancer. J Mammary Gland Biol Neoplasia (2008) 13:351–352 DOI 10.1007/s10911-008-9096-2