title: STAT1-deficient mice spontaneously develop estrogen receptor α-positive luminal mammary carcinomas.
abstract: BACKGROUND
  Although breast cancers expressing estrogen receptor-α (ERα) and progesterone receptors (PR) are the most common form of mammary malignancy in humans, it has been difficult to develop a suitable mouse model showing similar steroid hormone responsiveness. STAT transcription factors play critical roles in mammary gland tumorigenesis, but the precise role of STAT1 remains unclear. Herein, we show that a subset of human breast cancers display reduced STAT1 expression and that mice lacking STAT1 surprisingly develop ERα+/PR+ mammary tumors.
  
  
  METHODS
  We used a combination of approaches, including histological examination, gene targeted mice, gene expression analysis, tumor transplantaion, and immunophenotyping, to pursue this study.
  
  
  RESULTS
  Forty-five percent (37/83) of human ERα+ and 22% (17/78) of ERα- breast cancers display undetectable or low levels of STAT1 expression in neoplastic cells. In contrast, STAT1 expression is elevated in epithelial cells of normal breast tissues adjacent to the malignant lesions, suggesting that STAT1 is selectively downregulated in the tumor cells during tumor progression. Interestingly, the expression levels of STAT1 in the tumor-infiltrating stromal cells remain elevated, indicating that single-cell resolution analysis of STAT1 level in primary breast cancer biopsies is necessary for accurate assessment. Female mice lacking functional STAT1 spontaneously develop mammary adenocarcinomas that comprise > 90% ERα+/PR+ tumor cells, and depend on estrogen for tumor engraftment and progression. Phenotypic marker analyses demonstrate that STAT1-/- mammary tumors arise from luminal epithelial cells, but not myoepithelial cells. In addition, the molecular signature of the STAT1-/- mammary tumors overlaps closely to that of human luminal breast cancers. Finally, introduction of wildtype STAT1, but not a STAT1 mutant lacking the critical Tyr701 residue, into STAT1-/- mammary tumor cells results in apoptosis, demonstrating that the tumor suppressor function of STAT1 is cell-autonomous and requires its transcriptional activity.
  
  
  CONCLUSIONS
  Our findings demonstrate that STAT1 suppresses mammary tumor formation and its expression is frequently lost during breast cancer progression. Spontaneous mammary tumors that develop in STAT1-/- mice closely recapitulate the progression, ovarian hormone responsiveness, and molecular characteristics of human luminal breast cancer, the most common subtype of human breast neoplasms, and thus represent a valuable platform for testing novel treatments and detection modalities.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, 425 S, Euclid Avenue, St, Louis, MO 63110, USA.
authors.forename: Szeman Ruby
authors.initials: SR
authors.lastname: Chan
authors.forename: William
authors.initials: W
authors.lastname: Vermi
authors.forename: Jingqin
authors.initials: J
authors.lastname: Luo
authors.forename: Laura
authors.initials: L
authors.lastname: Lucini
authors.forename: Charles
authors.initials: C
authors.lastname: Rickert
authors.forename: Amy M
authors.initials: AM
authors.lastname: Fowler
authors.forename: Silvia
authors.initials: S
authors.lastname: Lonardi
authors.forename: Cora
authors.initials: C
authors.lastname: Arthur
authors.forename: Larry Jt
authors.initials: LJ
authors.lastname: Young
authors.forename: David E
authors.initials: DE
authors.lastname: Levy
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Welch
authors.forename: Robert D
authors.initials: RD
authors.lastname: Cardiff
authors.forename: Robert D
authors.initials: RD
authors.lastname: Schreiber
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism*; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D016000:Cluster Analysis; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D015536:Down-Regulation; D004847:Epithelial Cells / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D053208:Kaplan-Meier Estimate; D042361:Mammary Glands, Human / Q000378:metabolism / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D012189:Retrospective Studies; D050794:STAT1 Transcription Factor / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D018719:Erb-b2 Receptor Tyrosine Kinases; D011980:Receptors, Progesterone; D050794:STAT1 Transcription Factor; C499308:Rag2 protein, mouse; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; C097314:progesterone receptor B; C508053:ERBB2 protein, human