Hormonal interactions during mammary gland development

Mammary morphogenesis is the result of the complex interplay of prolactin (PRL), estrogen (E), progesterone (P) and growth factors. The spatio-temporal patterns of hormone and growth factor action on the epithelial and stromal compartments during development and differentiation of the mammary gland give vital clues to cell fate. Concurrent with the morphological changes in the gland during puberty, progesterone receptors (PR) localize at early branch points. During peripubertal morphogenesis PR distribution shifts from a homogeneous to a heterogeneous pattern The Hox-related, homeobox containing gene, Msx2, is highly expressed during branching morphogenesis where our studies in vivo and in vitro show that its expression is regulated by P in the presence of E. The overexpression of Msx-2 in stable transfectants of the 'normal' mouse mammary epithelial cell line, NmuMg, results in a highly branched phenotype compared with control cells transfected with the empty vector (EV) when grown in collagen gels. The NmuMg-Msx2 cells constitutively overexpress cyclin D₁ and form multiple large colonies when grown in soft agar. When the NmuMg-Msx2 were implanted into nude mice either subcutaneously or in the mammary fat pad, rapidly growing tumors arise within 8 weeks in 97% of the mice compared with small, slow-growing tumors in 42% of animals given the NmuMg-EV cells. PRL, in concert with P, acts during ductal branching and alveologenesis within the mammary gland. As the animal matures, the distribution of the PRL receptor in the epithelium, like that of the PR, progresses from a homogeneous to a heterogeneous pattern, supporting our hypothesis that these hormones synergize to stimulate epithelial and stromal proliferation.