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.
Highlights
Breast cancer is heterogeneous in its genetic makeup and multifaceted in etiology [1, 2]
MYB knockdown in vivo Having established that MYB is required for proliferation of human estrogen receptor (ER)-positive breast cancer cells in vitro [6], we asked here whether persistent expression was required for established tumors
Tumors were established orthotopically for 2 weeks before short hairpin RNA (shRNA) expression was induced with doxycycline (Fig. 1A); subsequent monitoring (Fig. 1B and C) showed that MYB expression is required for ongoing tumor growth
Summary
Breast cancer is heterogeneous in its genetic makeup and multifaceted in etiology [1, 2]. The majority of breast cancers express one or more of these receptors, some are "triple-negative" [3]; this subtype is often more aggressive and does not respond to conventional adjuvant therapies that target the above-mentioned receptors [4, 5]. With such phenotypic diversity, the prospect of identifying molecular points of convergence that drive breast cancer may seem small enticing. Authors' Affiliations: 1Peter MacCallum Cancer Centre and Department of Pathology, University of Melbourne, Melbourne, Victoria; and 2University of Queensland Diamantina Institute, Brisbane, Queensland, Australia.
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