title: RUNX2 correlates with subtype-specific breast cancer in a human tissue microarray, and ectopic expression of Runx2 perturbs differentiation in the mouse mammary gland.
abstract: RUNX2, a master regulator of osteogenesis, is oncogenic in the lymphoid lineage; however, little is known about its role in epithelial cancers. Upregulation of RUNX2 in cell lines correlates with increased invasiveness and the capacity to form osteolytic disease in models of breast and prostate cancer. However, most studies have analysed the effects of this gene in a limited number of cell lines and its role in primary breast cancer has not been resolved. Using a human tumour tissue microarray, we show that high RUNX2 expression is significantly associated with oestrogen receptor (ER)/progesterone receptor (PR)/HER2-negative breast cancers and that patients with high RUNX2 expression have a poorer survival rate than those with negative or low expression. We confirm RUNX2 as a gene that has a potentially important functional role in triple-negative breast cancer. To investigate the role of this gene in breast cancer, we made a transgenic model in which Runx2 is specifically expressed in murine mammary epithelium under the control of the mouse mammary tumour virus (MMTV) promoter. We show that ectopic Runx2 perturbs normal development in pubertal and lactating animals, delaying ductal elongation and inhibiting lobular alveolar differentiation. We also show that the Runx2 transgene elicits age-related, pre-neoplastic changes in the mammary epithelium of older transgenic animals, suggesting that elevated RUNX2 expression renders such tissue more susceptible to oncogenic changes and providing further evidence that this gene might have an important, context-dependent role in breast cancer.
authors.affiliation: Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow, G61 1BD, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: McDonald
authors.forename: Nicola
authors.initials: N
authors.lastname: Ferrari
authors.forename: Anne
authors.initials: A
authors.lastname: Terry
authors.forename: Margaret
authors.initials: M
authors.lastname: Bell
authors.forename: Zahra M
authors.initials: ZM
authors.lastname: Mohammed
authors.forename: Clare
authors.initials: C
authors.lastname: Orange
authors.forename: Alma
authors.initials: A
authors.lastname: Jenkins
authors.forename: William J
authors.initials: WJ
authors.lastname: Muller
authors.forename: Barry A
authors.initials: BA
authors.lastname: Gusterson
authors.forename: James C
authors.initials: JC
authors.lastname: Neil
authors.forename: Joanne
authors.initials: J
authors.lastname: Edwards
authors.forename: Joanna S
authors.initials: JS
authors.lastname: Morris
authors.forename: Ewan R
authors.initials: ER
authors.lastname: Cameron
authors.forename: Karen
authors.initials: K
authors.lastname: Blyth
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000145:classification* / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D006801:Humans; D006965:Hyperplasia; D007774:Lactation; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology*; D008324:Mammary Tumor Virus, Mouse / Q000502:physiology; D008822:Mice, Transgenic; D008875:Middle Aged; D010298:Parity; D011230:Precancerous Conditions / Q000473:pathology; D011247:Pregnancy; D050799:STAT5 Transcription Factor / Q000378:metabolism; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D004268:DNA-Binding Proteins; C500759:Elf5 protein, mouse; C493709:RUNX2 protein, human; C493716:Runx2 protein, mouse; D050799:STAT5 Transcription Factor; D014157:Transcription Factors
keywords: Breast cancer; Mammary development; RUNX2; Transgenic model