Prolactin gene-disruption arrests mammary gland development and retards T-antigen-induced tumor growth

Prolactin (PRL), interacting with other hormones from the pituitary, gonad, and placenta, activates specific signals that drive the appropriately time d morphological and functional development of the mammary gland. A mouse mo del of isolated PRL deficiency (PRL-/-) was created by gene disruption in a n effort to further understand the molecular basis of mammary gland develop ment and breast cancer. Whereas primary ductal growth was normal in PRL-/- mice, ductal arborization was minimal (branches/mm(2) = 1.5+/-0.5), and lob ular budding was absent. Replacement therapy with PBL injections stimulated a modest degree of lobular budding and ductal arborization (3.75+/-0.9). P ituitary transplants to the kidney capsule of PRL-/- mice restored lobular budding and ductal arborization, to the full extent of that seen in control animals (20.3+/-5.5). Pregnancy, established by mating progesterone-treate d PRL-/- females with PRL-/- males, led to complete morphological developme nt of the mammary gland, appropriate to the gestational stage. PRL treatmen t stimulated tyrosine phosphorylation and DNA binding activity of Stat5a, b ut not Stat1 in PRL-/- or PRL+/- females, and Stat5a, but not Stat1, was el evated by estradiol within 24 h, PRL-deficient mice were crossed with mice expressing a dominant oncogene (polyoma middle-T antigen driven by the MMTV promoter, PyVT mice). Palpable (1 mm(3)) tumors were detected an average o f 9 days earlier in hormonally normal females (PRL+/-:PyVT) compared with l ittermates that were PRL-deficient (PRL-/-:PyVT). The growth rate of PyVT-i nduced tumors was 30% faster in PRL+/-, than in PRL-/- females.