Prolactin activates ERα in the absence of ligand in female mammary development and carcinogenesis in vivo.
Resistance of estrogen receptor positive (ERα+) breast cancers to antiestrogens is a major factor in the mortality of this disease. Although activation of ERα in the absence of ligand is hypothesized to contribute to this resistance, the potency of this mechanism in vivo is not clear. Epidemiologic studies have strongly linked prolactin (PRL) to both development of ERα+ breast cancer and resistance to endocrine therapies. Here we employed genetically modified mouse models to examine the ability of PRL and cross talk with TGFα to activate ERα, using a mutated ERα, ERα(G525L), which is refractory to endogenous estrogens. We demonstrate that PRL promotes pubertal ERα-dependent mammary ductal elongation and gene expression in the absence of estrogen, which are abrogated by the antiestrogen, ICI 182,780 (ICI). PRL and TGFα together reduce sensitivity to estrogen, and 30% of their combined stimulation of ductal proliferation is inhibited by ICI, implicating ligand-independent activation of ERα as a component of their interaction. However, PRL/TGFα-induced heterogeneous ERα+ tumors developed more rapidly in the presence of ICI and contained altered transcripts for surface markers associated with epithelial subpopulations and increased signal transducer and activator of transcription 5b expression. Together, these data support strong interactions between PRL and estrogen on multiple levels. Ligand-independent activation of ERα suggests that PRL may contribute to resistance to antiestrogen therapies. However, these studies also underscore ERα-mediated moderation of tumor phenotype. In light of the high expression of PRL receptors in ERα+ cancers, understanding the actions of PRL and cross talk with other oncogenic factors and ERα itself has important implications for therapeutic strategies.
Department of Comparative Biosciences, 2015 Linden Drive, University of Wisconsin-Madison, Madison, WI 53706. schulerl@svm.vetmed.wisc.edu.
Kathleen A
KA
O'Leary
Fatou
F
Jallow
Debra E
DE
Rugowski
Ruth
R
Sullivan
Kerstin W
KW
Sinkevicius
Geoffrey L
GL
Greene
Linda A
LA
Schuler
D000375:Aging; D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D000077267:Fulvestrant; D008321:Mammary Glands, Animal / Q000254:growth & development* / Q000378:metabolism*; D015674:Mammary Neoplasms, Animal / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D011388:Prolactin / Q000494:pharmacology*; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism
D047628:Estrogen Receptor alpha; D016211:Transforming Growth Factor alpha; D000077267:Fulvestrant; D004958:Estradiol; D011388:Prolactin