Tumors that express estrogen receptor alpha (ERalpha+) comprise 75% of breast cancers in women. While treatments directed against this receptor have successfully lowered mortality rates, many primary tumors initially or later exhibit resistance. The paucity of murine models of this "luminal" tumor subtype has hindered studies of factors that promote their pathogenesis and modulate responsiveness to estrogen-directed therapeutics. Since epidemiologic studies closely link prolactin and the development of ERalpha+ tumors in women, we examined characteristics of the aggressive ERalpha+ and ERalpha- carcinomas which develop in response to mammary prolactin in a murine transgenic model (neu-related lipocalin - prolactin (NRL-PRL)). To evaluate their relationship to clinical tumors, we determined phenotypic relationships among these carcinomas, other murine models of breast cancer, and features of luminal tumors in women.

We examined a panel of prolactin-induced tumors for characteristics relevant to clinical tumors: histotype, ERalpha/ progesterone receptor (PR) expression and estrogen responsiveness, p signal transducers and activator of transcription 5 (Stat5), Activating Protein 1 (AP-1) components, p extracellular signal regulated kinase (ERK) 1/2 and pAKT. We compared levels of transcripts in the ERalpha-associated "luminal" signature that defines this subtype of tumors in women and transcripts enriched in various mammary epithelial lineages to other well-studied genetically modified murine models of breast cancer. Finally, we used microarray analyses to compare prolactin-induced ERalpha+ and ERalpha- tumors, and examined responsiveness to estrogen and the antiestrogen, Fulvestrant, in vivo.

Prolactin-induced carcinomas were markedly diverse with respect to histotype, ERalpha/PR expression, and activated signaling cascades. They constituted a heterogeneous, but distinct group of murine mammary tumors, with molecular features of the luminal subtype of human breast cancer. In contrast to morphologically normal and hyperplastic structures in NRL-PRL females, carcinomas were insensitive to ERalpha-mediated signals. These tumors were distinct from mouse mammary tumor virus (MMTV)-neu tumors, and contained elevated transcripts for factors associated with luminal/ alveolar expansion and differentiation, suggesting that they arose from physiologic targets of prolactin. These features were shared by ERalpha+ and ERalpha- tumors, suggesting a common origin, although the former exhibited transcript profiles reflecting greater differentiation.

Our studies demonstrate that prolactin can promote diverse carcinomas in mice, many of which resemble luminal breast cancers, providing a novel experimental model to examine the pathogenesis, progression and treatment responsiveness of this tumor subtype.

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