title: MYB is essential for mammary tumorigenesis.
abstract: MYB oncogene upregulation is associated with estrogen receptor (ER)-positive breast cancer, but disease requirements for MYB function in vivo have not been explored. In this study, we provide evidence of a critical requirement for MYB functions in models of human and murine breast cancer. In human breast cancer, we found that MYB expression was critical for tumor cell growth both in vitro and in vivo in xenograft settings. In transgenic knockout mice, tissue-specific deletion of the murine MYB gene caused a transient defect in mammary gland development that was reflected in delayed ductal branching and defective apical bud formation. In mouse mammary tumor virus (MMTV)-NEU mice where tumors are initiated by activation of HER2, MYB deletion was sufficient to abolish tumor formation. In the more aggressive MMTV-PyMT model system, MYB deletion delayed tumorigenesis significantly. Together, the findings in these transgenic knockout models implied that MYB was critical during an early window in mammary development when it was essential for tumor initiation, even though MYB loss did not exert a lasting impact upon normal mammary function. Two important MYB-target genes that promote cell survival, BCL2 and GRP78/BIP, were each elevated compared with nontransformed mammary epithelial cells, thereby promoting survival as confirmed in colony formation assays in vitro. Taken together, our findings establish a role for MYB at the hub of ER- and HER2-dependent pathways in mammary carcinogenesis.
authors.affiliation: Peter MacCallum Cancer Centre and Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Rebecca Yu
authors.initials: RY
authors.lastname: Miao
authors.forename: Yvette
authors.initials: Y
authors.lastname: Drabsch
authors.forename: Ryan Stanley
authors.initials: RS
authors.lastname: Cross
authors.forename: Dane
authors.initials: D
authors.lastname: Cheasley
authors.forename: Sandra
authors.initials: S
authors.lastname: Carpinteri
authors.forename: Lloyd
authors.initials: L
authors.lastname: Pereira
authors.forename: Jordane
authors.initials: J
authors.lastname: Malaterre
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Gonda
authors.forename: Robin L
authors.initials: RL
authors.lastname: Anderson
authors.forename: Robert G
authors.initials: RG
authors.lastname: Ramsay
mesh_terms: D000818:Animals; D000957:Antigens, Viral, Tumor / Q000235:genetics; D045744:Cell Line, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; D047628:Estrogen Receptor alpha / Q000032:analysis; D005038:Ethylnitrosourea; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000737:chemistry / Q000209:etiology*; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D020626:Oncogene Proteins v-myb / Q000502:physiology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis
chemical_list: D000957:Antigens, Viral, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; D047628:Estrogen Receptor alpha; D005038:Ethylnitrosourea; D020626:Oncogene Proteins v-myb; D018719:Erb-b2 Receptor Tyrosine Kinases; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse