Human Cancer Biology CIP2A Is Associated with Human Breast Cancer Aggressivity

Purpose: To investigate the clinical relevance of the recently characterized human oncoprotein cancerous inhibitor of protein phosphatase 2A (CIP2A) in human breast cancer. Experimental Design: 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. Results: CIP2A mRNA is overexpressed (n = 159) and correlates with higher ScarffBloom-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 anchorageindependent growth in breast cancer cells. Finally, CIP2A was shown to support MDA-MB-231 xenograft growth in nude mice. Conclusions: 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. (Clin Cancer Res 2009;15(16):5092–100) Breast cancer is the most common malignancy that affects women, with >1 million cases occurring worldwide annually. Further, breast cancer is the most important cause of cancerrelated deaths in women. However, the understanding of the molecular mechanisms that maintain the malignant growth of breast cancer cells remains incomplete (1). The oncogenic transformation of human cells requires the perturbation of a distinct set of oncogenes and tumor suppressors (2). It was recently shown that the tumor suppressor activity of protein phosphatase 2A (PP2A) prevents the transformation of human breast epithelial cells (3). The role of PP2A as a relevant breast cancer tumor suppressor was further strengthened by a recent study showing that somatic mutations occurred in one of the subunits of the functional PP2A trimer (PP2A Aβ) in 13% of human breast cancers and that PP2A trimers containing this mutation fail to suppress the oncogenic activity of RalA (4, 5). In Authors' Affiliations: Centre for Biotechnology, University of Turku and Åbo Akademi University; VTT, Technical Research Centre, Turku, Finland; Institut de Recherche en Cancérologie de Montpellier, CRLC Val d'Aurelle-Paul Lamarque, Montpellier, France; Institute for Molecular Medicine Finland, University of Helsinki, Finland; Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; and Institute of Medical Technology, University of Tampere, and Tampere University Hospital, Tampere, Finland Received 12/19/08; revised 4/30/09; accepted 5/14/09; published OnlineFirst 8/11/09. Grant support: Academy of Finland project 1121413; Competitive Research Funding from the Pirkanmaa Hospital District; Emil Aaltonen Foundation, Sigrid Jusélius Foundation, and Finnish Cancer Society; Academy of Finland postdoctorate fellowship 122546 (C. Côme); Ligue contre le Cancer-Comité Hérault fellowship (M. Chanrion); Cancer Organizations of Finland, Sigrid Juselius Foundation, and Academy of Finland (Centres of Excellence funding 213502; H. Edgren and O. Kallioniemi); Finnish Cancer Institute, Finnish Cancer Organisations, Ida Montin Foundation, and Hilda Kauhanen Foundation (E. Mattila and J. Ivaska); Netherlands Organization for Scientific Research grant ZonMw 917.036.347 and Dutch Cancer Society grant NKI 2002-2635 (X. Liu and J. Jonkers); Institut National de la Santé et de la Recherche Médicale (J.-M. Darbon); and CRLC Val d'Aurelle-Paul Lamarque (S. Thézenas). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). J. Westermarck is a research professor for the Finnish Cancer Institute. Requests for reprints: Jukka Westermarck, Centre for Biotechnology, University of Turku and Åbo Akademi University, Tykistökatu 6A, 20520 Turku, Finland. Phone: 358407423007; Fax: 35823338000; E-mail: [email protected]. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-08-3283 5092 Clin Cancer Res 2009;15(16) August 15, 2009 www.aacrjournals.org Research. on May 3, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst August 11, 2009; DOI: 10.1158/1078-0432.CCR-08-3283