Abstract 3696: Biological significance of the wild-type p53-induced phosphatase 1(Wip1) expression in invasive breast cancer
Authors: Inoue Yuka , Yamashita Nami , Tokunaga Eriko , Kitao Hiroyuki , Tanaka Kimihiro , Ueo Hiroki , Saeki Hiroshi , Oki Eiji , Maehara Yoshihiko 
Published: July 2016

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 (DDR) network. Wip1 is encoded by the protein phosphatase magnesium dependent 1 delta (PPM1D), sited on locus 17q23. PPM1D amplification has been reported in breast cancer.

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 cells (MCF7, T47D, MDA-MB231, HCC1937, HS578T, BT20 and SKBr3) were used for Wip1 expression analysis and copy number analysis. Primary invasive ductal carcinoma specimens were obtained from Japanese patients who underwent surgery without neoadjuvant chemotherapy or endocrine therapy. Wip1 mRNA expression was evaluated in 140 cases by quantitative reverse transcriptase-polymerase chain reaction (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 the single-nucleotide polymorphism-Comparative Genomic Hybridization (SNP-CGH) array in 12 cases. The effects on the cell growth of the Wip1 inhibitor (GSK2830371) was analyzed by the viability assay in MCF7.

Results Wip1 mRNA expression was significantly higher in MCF7, luminal type cell line. Wip1 mRNA expression was divided into four groups, very high, high, low and very low. The very high Wip1 mRNA expression was significantly associated with positive estrogen receptor (ER) expression (p = 0.02). There was no significant correlation between Wip1 mRNA expression and the prognosis. Wip1 protein nuclear expression was positive in 21 cases (10.9%). 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). Amplification at 17q23 was detected in 6 cases by SNP-CGH array, and all of these six cases showed positive nuclear Wip1 expression. PPM1D amplification was not observed in Wip1 negative cases. In the cell viability assay, the suppression of the MCF7 cell growth was observed by Wip1 inhibitor.

Conclusions Wip1 nuclear protein expression may be regulated by PPM1D amplification, and the Wip1 inhibitor may have the therapeutic effects for the breast cancer with PPM1D amplification or high Wip1 protein expression.

Citation Format: Yuka Inoue, Nami Yamashita, Eriko Tokunaga, Hiroyuki Kitao, Kimihiro Tanaka, Hiroki Ueo, Hiroshi Saeki, Eiji Oki, Yoshihiko Maehara. Biological significance of the wild-type p53-induced phosphatase 1(Wip1) expression in invasive breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3696.