Abstract | INTRODUCTION:
Tumors that express estrogen receptor alpha (ERα+) 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 ERα+ tumors in women, we examined characteristics of the aggressive ERα+ and ERα- 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. METHODS: RESULTS:
Prolactin-induced carcinomas were markedly diverse with respect to histotype, ERα/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 ERα-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 ERα+ and ERα- tumors, suggesting a common origin, although the former exhibited transcript profiles reflecting greater differentiation. CONCLUSIONS: 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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Authors | Lisa M Arendt, Debra E Rugowski, Tara A Grafwallner-Huseth, Maria Jose Garcia-Barchino, Hallgeir Rui, Linda A Schuler |
Journal | Breast cancer research : BCR
(Breast Cancer Res)
Vol. 13
Issue 1
Pg. R11
(Jan 28 2011)
ISSN: 1465-542X [Electronic] England |
PMID | 21276249
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Biomarkers, Tumor
- Estrogen Receptor alpha
- Estrogens
- STAT5 Transcription Factor
- Transcription Factor AP-1
- Prolactin
- Proto-Oncogene Proteins c-akt
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Topics |
- Animals
- Biomarkers, Tumor
(genetics)
- Breast Neoplasms
(genetics, metabolism)
- Carcinoma
(genetics, metabolism)
- Cluster Analysis
- Disease Models, Animal
- Epithelial Cells
(metabolism)
- Estrogen Receptor alpha
(genetics, metabolism)
- Estrogens
(physiology)
- Female
- Gene Expression Profiling
- Humans
- Male
- Mammary Neoplasms, Experimental
(etiology, genetics, metabolism)
- Mice
- Mice, 129 Strain
- Mice, Inbred C57BL
- Mice, Transgenic
- Prolactin
(genetics, metabolism)
- Proto-Oncogene Proteins c-akt
(metabolism)
- STAT5 Transcription Factor
(metabolism)
- Transcription Factor AP-1
(metabolism)
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