Prolactin promotes mammary pathogenesis independently from cyclin D1.
Epidemiological and experimental studies have revealed an important role for prolactin (PRL) in breast cancer. Cyclin D1 is a major downstream target of PRL in lobuloalveolar development during pregnancy and is amplified and/or overexpressed in many breast carcinomas. To examine the importance of cyclin D1 in PRL-induced pathogenesis, we generated transgenic mice (NRL-PRL) that overexpress PRL in mammary epithelial cells, with wild-type, heterozygous, or genetically ablated cyclin D1 in the FVB/N genetic background. Although loss of one cyclin D1 allele did not affect PRL-induced mammary lesions in nonparous females, the complete absence of cyclin D1 (D1(-/-)) markedly decreased tumor incidence. Nevertheless, NRL-PRL/D1(-/-) females developed significantly more preneoplastic lesions (eg, epithelial hyperplasias and mammary intraepithelial neoplasias) than D1(-/-) females. Moreover, although lack of cyclin D1 reduced proliferation of morphologically normal mammary epithelium, transgenic PRL restored it to rates of wild-type females. PRL posttranscriptionally increased nuclear cyclin D3 protein in D1(-/-) luminal cells, indicating one compensatory mechanism. Consistently, pregnancy induced extensive lobuloalveolar growth in the absence of cyclin D1. However, transcripts for milk proteins were reduced, and pups failed to survive, suggesting that mammary differentiation was inadequate. Together, these results indicate that cyclin D1 is an important, but not essential, mediator of PRL-induced mammary proliferation and pathology in FVB/N mice and is critical for differentiation and lactation.
Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA.
Jennifer M
JM
Asher
Kathleen A
KA
O'Leary
Debra E
DE
Rugowski
Lisa M
LM
Arendt
Linda A
LA
Schuler
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D019938:Cyclin D1 / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D056743:Cyclin D3 / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D007774:Lactation / Q000502:physiology; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000378:metabolism / Q000502:physiology; D011230:Precancerous Conditions / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D011388:Prolactin / Q000378:metabolism / Q000502:physiology*
C530105:Ccnd1 protein, mouse; C534697:Ccnd3 protein, mouse; D056743:Cyclin D3; D047628:Estrogen Receptor alpha; D009363:Neoplasm Proteins; D019938:Cyclin D1; D004958:Estradiol; D011388:Prolactin