Yu, M., Lin, G., Arshadi, N., Kalatskaya, I., Xue, B., Haider, S., Nguyen, F., Boutros, P. C., Elson, A., Muthuswamy, L. B., Tonks, N. K., Muthuswamy, S. K. (October 2012) Expression profiling during mammary epithelial cell 3D morphogenesis identifies PTPRO as a novel regulator of morphogenesis and ErbB2 mediated transformation. Mol Cell Biol, 32 (19). pp. 3913-3924. ISSN 1098-5549 (Electronic)0270-7306 (Linking)
Abstract
Identification of genes that are upregulated during mammary epithelial cell morphogenesis may reveal novel regulators of tumorigenesis. We have demonstrated that gene expression programs in mammary epithelial cells grown in monolayer cultures differ significantly from those in 3D cultures. We identify a protein tyrosine phosphate, PTPRO that was upregulated in mature MCF-10A mammary epithelial 3D structures but low to undetectable levels in monolayer cultures. Downregulation of PTPRO by RNA interference inhibited proliferation arrest during morphogenesis. Low levels of PTPRO expression correlated with reduced survival for breast cancer patients, suggesting a tumor suppressor function. Furthermore, we showed that the receptor tyrosine kinase ErbB2/HER2 is a direct substrate of PTPRO and that loss of PTPRO increased ErbB2-induced cell proliferation and transformation, together with tyrosine phosphorylation of ErbB2. Moreover, in patients with ErbB2-positive breast tumors, low PTPRO expression correlated with poor clinical prognosis compared to ErbB2 positive patients with high levels of PTPRO. Thus, PTPRO is a novel regulator of ErbB2 signaling, a potential tumor suppressor and a novel prognostic marker for patients with ErbB2-positive breast cancers.
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