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

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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Acknowledgements

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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