Abstract
Prolactin (PRL), interacting with other hormones from the pituitary, gonad, and placenta, activates specific signals that drive the appropriately timed morphological and functional development of the mammary gland. A mouse model of isolated PRL deficiency (PRL−/−) was created by gene disruption in an effort to further understand the molecular basis of mammary gland development and breast cancer. Whereas primary ductal growth was normal in PRL−/− mice, ductal arborization was minimal (branches/mm2=1.5±0.5), and lobular budding was absent. Replacement therapy with PRL injections stimulated a modest degree of lobular budding and ductal arborization (3.75±0.9). Pituitary 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-treated PRL−/− females with PRL−/− males, led to complete morphological development of the mammary gland, appropriate to the gestational stage. PRL treatment stimulated tyrosine phosphorylation and DNA binding activity of Stat5a, but not Stat1 in PRL−/− or PRL+/− females, and Stat5a, but not Stat1, was elevated 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 mm3) tumors were detected an average of 9 days earlier in hormonally normal females (PRL+/−:PyVT) compared with littermates that were PRL-deficient (PRL−/−:PyVT). The growth rate of PyVT-induced tumors was 30% faster in PRL+/−, than in PRL−/− females.
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This work was supported by a grant from the National Institute of Diabetes, Digestive, and Kidney Diseases, and a Faculty Development Award from Beaver College, Glenside, PA, USA.
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Vomachka, A., Pratt, S., Lockefeer, J. et al. Prolactin gene-disruption arrests mammary gland development and retards T-antigen-induced tumor growth. Oncogene 19, 1077–1084 (2000). https://doi.org/10.1038/sj.onc.1203348
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DOI: https://doi.org/10.1038/sj.onc.1203348
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