Abstract
To investigate the clinical relevance of the recently characterized human oncoprotein cancerous inhibitor of protein phosphatase 2A (CIP2A) in human breast cancer. CIP2A expression (mRNA and protein) was measured in three different sets of human mammary tumors and compared with clinicopathologic variables. The functional role of CIP2A in breast cancer cells was evaluated by small interfering RNA-mediated depletion of the protein followed by an analysis of cell proliferation, migration, anchorage-independent growth, and xenograft growth. CIP2A mRNA is overexpressed (n = 159) and correlates with higher Scarff-Bloom-Richardson grades (n = 251) in samples from two independent human breast cancer patients. CIP2A protein was found to be overexpressed in 39% of 33 human breast cancer samples. Furthermore, CIP2A mRNA expression positively correlated with lymph node positivity of the patients and with the expression of proliferation markers and p53 mutations in the tumor samples. Moreover, CIP2A protein expression was induced in breast cancer mouse models presenting mammary gland-specific depletion of p53 and either BRCA1 or BRCA2. Functionally, CIP2A depletion was shown to inhibit the expression of its target protein c-Myc. Loss of CIP2A also inhibited anchorage-independent growth in breast cancer cells. Finally, CIP2A was shown to support MDA-MB-231 xenograft growth in nude mice. Our data show that CIP2A is associated with clinical aggressivity in human breast cancer and promotes the malignant growth of breast cancer cells. Thus, these results validate the role of CIP2A as a clinically relevant human oncoprotein and warrant further investigation of CIP2A as a therapeutic target in breast cancer treatment.
Highlights
To investigate the clinical relevance of the recently characterized human oncoprotein cancerous inhibitor of protein phosphatase 2A (CIP2A) in human breast cancer
Mucinous carcinomas, which are mammary tumors with a good prognosis, displayed CIP2A mRNA expression at a level that is comparable with expression levels in normal breast samples and significantly lower than in the invasive invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), and IDC with intraductal comedo carcinoma tumors (P < 0.044; Fig. 1B)
CIP2A was recently identified as a human oncoprotein based on its capacity to transform human immortalized cells, its overexpression in human head and neck squamous cell carcinomas and colon cancer, and its capacity to promote tumor growth [11]
Summary
To investigate the clinical relevance of the recently characterized human oncoprotein cancerous inhibitor of protein phosphatase 2A (CIP2A) in human breast cancer. We show that CIP2A expression strongly correlates with aggressive characteristics of human breast cancer tumors (high ScarffBloom-Richardson grade, lymph node positivity, and expression of proliferation markers). These results show for the first time that CIP2A expression is linked with clinical markers of aggressivity in human cancer. We show that CIP2A depletion decreases the proliferation of human breast cancer cell lines and inhibits the growth of xenograft MDA-MB-231 cells in vivo These results warrant further investigation of CIP2A as a therapeutic target in the treatment of breast cancer
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