Abstract P1-08-13: The clinical importance of nuclear wild-type p53-induced phosphatase 1(Wip1) expression in breast cancer patients
Authors: Inoue Y , Yamashita N , Tokunaga E , Kitao H , Tanaka K , Saeki H , Oki E , Maehara Y 
Published: March 2017

Backgrounds; The wild-type p53-induced phosphatase 1(Wip1) is a member of the serine/threonine protein phosphatases, and plays an important role in the nucleus as one of the key components in the DNA damage response network. Wip1 is encoded by the protein phosphatase magnesium dependent 1 delta (PPM1D), sited on locus 17q23. PPM1D gene amplification and/or Wip1 expression have been observed in numerous tumors, including breast cancer. PPM1D is referred to as oncogene, as Wip1 inhibits phosphorylation of p53 and work as a negative regulator in cell death. Inhibition of Wip1 may have an important therapeutic role in suppressing tumor growth and evolution.

Aims; We evaluated the expression of Wip1 mRNA, Wip1 protein and PPM1D DNA copy number to clarify the relationship between Wip1 expression and the clinicopathological features and prognosis to determine the biological significance of Wip1.

Materials and Methods; Breast cancer cell lines (MCF7, T47D, MDA-MB231, HCC1937, HS578T, BT20 and SKBr3) were used for Wip1 expression analysis and copy number analysis. The specimens were obtained from Japanese breast cancer patients who underwent surgery without neoadjuvant chemotherapy or endocrine therapy in our department. Wip1 mRNA expression was evaluated in 140 cases by quantitative RT-PCR and Wip1 protein expression was evaluated in 192 cases by immunohistochemistry (IHC). The PPM1D DNA copy number was analyzed by genomic PCR in 33 breast cancer cases and by SNP-CGH array (Illumina, Human Omni 2.5-8) in 12 cases. The effects on the cell growth of the Wip1 inhibitor (GSK2830371) were analyzed by the viability assay in MCF7.

Results; Wip1 mRNA expression was signiﬁcantly higher in MCF7, luminal type cell line. There was no signiﬁcant correlation between Wip1 mRNA expression and prognosis. In IHC, positive nuclear Wip1 protein expression was detected in 21 cases (10.9%). There was no signiﬁcant correlation between Wip1 mRNA expression and Wip1 protein expression. There was no significant association between the Wip1 protein expression levels and the clinicopathological factors and the prognosis. PPM1D DNA copy number significantly correlated with Wip1 protein expression (p=0.0035). Copy number gain at 17q23 was detected in 6 cases by SNP-CGH array, and all of these six cases showed positive nuclear Wip1 expression. PPM1D copy number gain was not observed in Wip1 negative cases. In the cell viability assay, the MCF7 cell growth was suppressed by Wip1 inhibitor administration.

Conclusions;Wip1 protein expression in nucleus is important as oncogene, and its expression may be regulated by PPM1D copy number gain. Wip1 is considered to be the new therapeutic target for breast cancer patients.

Citation Format: Inoue Y, Yamashita N, Tokunaga E, Kitao H, Tanaka K, Saeki H, Oki E, Maehara Y. The clinical importance of nuclear wild-type p53-induced phosphatase 1(Wip1) expression in breast cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-08-13.