Abstract
Pubertal mammary growth in heifers is dependent on interactions of many hormones and growth factors of which some are stimulatory while others are inhibitory. Although estrogen and growth hormone (GH) are of primary importance, more recent studies have suggested a role for both systemic and mammary tissue-specific growth factors. Growth factors may act as mediators of estrogen and GH or through specific effects of their own. These growth factors include insulin (INS), IGFs (IGF-I and IGF-II), epidermal growth factor (EGF), FGFs (FGF-1 and FGF-2), TGFs (TGF-alpha and TGF-beta's, amphiregulin (AR), platelets derived growth factor (PDGF), and mammary derived growth factor-1 (MDGF-1). Using mammary epithelial cells derived from prepubertal heifers and cultured in three-dimensional collagen gels as an in vitro model, we have investigated the mitogenic effects of a number of different growth factors (IGF-I, des(1-3) IGF-I, IGF-II, INS, EGF, TGF-alpha, AR, FGF-1, FGF-2, and TGF-beta 1). As expected, IGF-I, des(1-3)IGF-I, IGF-II and INS all stimulated proliferation of mammary cells with des(1-3)IGF-I being the most potent and INS the least potent. The mitogenic effect of IGF-I could be inhibited by both IGFBP-2 and IGFBP-3 showing that these binding proteins modulate the bioactivity of IGF-I in the mammary gland at the cellular level. Regulation of IGF availability by IGFBPs in the extracellular environment therefore is critical for IGF action in the mammary gland. Proliferation of mammary epithelial cells was also stimulated by growth factors of the EGF family, i.e. EGF, TGF-alpha and AR, however, not as much as growth factors from the IGF family. Members of the fibroblast growth factor family showed various mitogenic activities. FGF-1 stimulated DNA synthesis while FGF-2 in concentrations above 10 ng/ml inhibited DNA synthesis. TGF-beta 1 at very low concentrations stimulated proliferation slightly whereas higher concentrations strongly inhibited proliferation of mammary epithelial cells and inhibited mitogenesis induced by growth factors of both the EGF- and IGF family. This shows that TGF-beta 1 is a very potent regulator of pubertal mammary growth.
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