| First Author | O'Leary KA | Year | 2013 |
| Journal | Endocrinology | Volume | 154 |
| Issue | 12 | Pages | 4483-92 |
| PubMed ID | 24064365 | Mgi Jnum | J:204060 |
| Mgi Id | MGI:5529544 | Doi | 10.1210/en.2013-1533 |
| Citation | O'Leary KA, et al. (2013) Prolactin activates ERalpha in the absence of ligand in female mammary development and carcinogenesis in vivo. Endocrinology 154(12):4483-92 |
| abstractText | Resistance of estrogen receptor positive (ERalpha+) breast cancers to antiestrogens is a major factor in the mortality of this disease. Although activation of ERalpha 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 ERalpha+ breast cancer and resistance to endocrine therapies. Here we employed genetically modified mouse models to examine the ability of PRL and cross talk with TGFalpha to activate ERalpha, using a mutated ERalpha, ERalpha(G525L), which is refractory to endogenous estrogens. We demonstrate that PRL promotes pubertal ERalpha-dependent mammary ductal elongation and gene expression in the absence of estrogen, which are abrogated by the antiestrogen, ICI 182,780 (ICI). PRL and TGFalpha together reduce sensitivity to estrogen, and 30% of their combined stimulation of ductal proliferation is inhibited by ICI, implicating ligand-independent activation of ERalpha as a component of their interaction. However, PRL/TGFalpha-induced heterogeneous ERalpha+ 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 ERalpha suggests that PRL may contribute to resistance to antiestrogen therapies. However, these studies also underscore ERalpha-mediated moderation of tumor phenotype. In light of the high expression of PRL receptors in ERalpha+ cancers, understanding the actions of PRL and cross talk with other oncogenic factors and ERalpha itself has important implications for therapeutic strategies. |
