Delineating the role of insulin-like growth factor binding protein 7 in mammary gland development

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Unlike many tissues in the body, mammary glands reach their full functional capacity after puberty. Upon puberty the mammary glands expand to create an elaborated network of ducts and small hollow sacs (alveolar structures). During pregnancy, the mammary gland undergoes further structural changes to create new ductal structures and enlarged alveolar sacs that contain milk-secreting cells and subsequently it recede to the pre-pregnant stage (involution). During lactation, the luminal cells will further differentiate into milk-producing cells while the myoepithelial cells, under the influence of oxytocin contract to induce milk ejection from the alveolar sacs into the ducts. The regeneration of mammary glands during each pregnancy cycle is due to the special functions of breast stem cells and their immediate progeny, the progenitor cells. While much studies have been done to understand the function of hormones such as estrogen, progesterone, prolactin, and growth factors such as insulin, Insulin-like Growth Factors (IGFs) and their binding proteins (Igfbps) in mammary gland development, very little is know about the potential roles that these factors play in regulating breast stem and progenitor cell functions. The overall objective of the proposed research program is the to ascertain the molecular mechanisms that regulate the special functions (proliferation, differentiation, and self-renewal) of breast stem cells. While the role of IGFs in mammary gland development and maturation has been described, the role of Igfbps in this process is not well understood. To ascertain the role of Igfbp7 in mammary gland development and maturation, we generated mice lacking expression of Igfbp7 protein. Interestingly, we have observed that in absence of Igfbp7, the development of mammary glands is significantly affected in otherwise healthy mice. Close examination of these mice revealed mammary gland developmental retardation at 3, 6 and 11 weeks of stage which coincide with pre and post pubertal stages of mammary gland development. Most significantly, we have observed that during pregnancy, the Igfbp7-null glands contained deformed and small alveolar structures and during lactation the Igfbp7-null glands exhibit signs of precocious involution. Also, we have observed that after 3 pregnancy cycles, the mammary glands of the Igfbp7-null mice contained no breast structures. This startling feature suggests that Igfpb7-null breast stem cells that are responsible for the regeneration of the breast structures may be functionally defective. In this research program we will examine if loss of Igfbp7 has affected the frequency and self-renewal capacity of the breast stem cells. Moreover, we will ascertain the molecular mechanisms involved in the Igfbp7 regulation of mammary gland development. This research program then will provide the first insight into how Igfbp7 acts to regulate the special functions of breast stem cells and mammary gland development. Because the role of Igfbp7 in the normal development of mammary gland has not been studied, any findings though the proposed work will further our knowledge about role of Igfbp7 in this complicated and highly coordinated process. This research program will also provide a great opportunity to train and retain highly-qualify personnel, as it requires the use of state of art equipment and acquiring unique skill sets in experimental procedures pertaining to the study of stem cells and mammary gland development that is lacking in the province of Manitoba and in Canada.