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Endocrinology. 2013 Dec;154(12):4483-92. doi: 10.1210/en.2013-1533. Epub 2013 Sep 24.

Prolactin activates ERα in the absence of ligand in female mammary development and carcinogenesis in vivo.

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  • 1Department of Comparative Biosciences, 2015 Linden Drive, University of Wisconsin-Madison, Madison, WI 53706. schulerl@svm.vetmed.wisc.edu.

Abstract

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.

PMID:
24064365
PMCID:
PMC3836081
DOI:
10.1210/en.2013-1533
[PubMed - indexed for MEDLINE]
Free PMC Article
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