title: Prolactin-induced mouse mammary carcinomas model estrogen resistant luminal breast cancer.
abstract: BACKGROUND
  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
  We examined a panel of prolactin-induced tumors for characteristics relevant to clinical tumors: histotype, ERα/progesterone receptor (PR) expression and estrogen responsiveness, Activating Protein 1 (AP-1) components, and phosphorylation of signal transducer and activator of transcription 5 (Stat5), extracellular signal regulated kinase (ERK) 1/2 and AKT. We compared levels of transcripts in the ERα-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 ERα+ and ERα- tumors, and examined responsiveness to estrogen and the anti-estrogen, Faslodex, in vivo.
  
  
  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.
authors.affiliation: Department of Comparative Biosciences, University of Wisconsin-Madison, 2015 Linden Dr., Madison, WI 53706, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Arendt
authors.forename: Debra E
authors.initials: DE
authors.lastname: Rugowski
authors.forename: Tara A
authors.initials: TA
authors.lastname: Grafwallner-Huseth
authors.forename: Maria Jose
authors.initials: MJ
authors.lastname: Garcia-Barchino
authors.forename: Hallgeir
authors.initials: H
authors.lastname: Rui
authors.forename: Linda A
authors.initials: LA
authors.lastname: Schuler
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism*; D016000:Cluster Analysis; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000502:physiology*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011388:Prolactin / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D047628:Estrogen Receptor alpha; D004967:Estrogens; D050799:STAT5 Transcription Factor; D018808:Transcription Factor AP-1; D011388:Prolactin; D051057:Proto-Oncogene Proteins c-akt