Data from <i>MYB</i> Is Essential for Mammary Tumorigenesis

Abstract

<div>Abstract<p><i>MYB</i> oncogene upregulation is associated with estrogen receptor (ER)-positive breast cancer, but disease requirements for MYB function <i>in vivo</i> 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 <i>in vitro</i> and <i>in vivo</i> in xenograft settings. In transgenic knockout mice, tissue-specific deletion of the murine <i>MYB</i> 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)-<i>NEU</i> mice where tumors are initiated by activation of HER2, <i>MYB</i> deletion was sufficient to abolish tumor formation. In the more aggressive MMTV-<i>PyMT</i> model system, <i>MYB</i> deletion delayed tumorigenesis significantly. Together, the findings in these transgenic knockout models implied that <i>MYB</i> 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, <i>BCL2</i> and <i>GRP78/BIP</i>, were each elevated compared with nontransformed mammary epithelial cells, thereby promoting survival as confirmed in colony formation assays <i>in vitro</i>. Taken together, our findings establish a role for MYB at the hub of ER- and HER2-dependent pathways in mammary carcinogenesis. <i>Cancer Res; 71(22); 7029–37. ©2011 AACR</i>.</p></div>