Abstract P3-06-11: TRIM39 is a poor prognostic factor for breast cancer patients and promotes proliferation and migration of breast cancer cells

Abstract

Abstract [Background] Tripartite motif-containing (TRIM) proteins typically function as E3 ubiquitin ligases and involved in many biological processes including cancer biology. We previously reported that TRIM25/Efp which stimulated the degradation of a negative cell-cycle regulator, 14-3-3 sigma,is a poor prognostic factor for breast cancer patients (Nature 417, 871, 2002; Clin Cancer Res 11, 6148, 2005) and that TRIM44 overexpressed in breast cancer enhanced NF-κB signaling (Int J Mol Sci 18, pii:E1931, 2017). In the present study, we focused on the prognostic value and the roles in breast cancer of a TRIM family protein, TRIM39. [Methods] Tissue samples of invasive breast cancer were obtained from 124 Japanese female primary breast cancer patients who underwent surgical treatment at Toranomon Hospital, Tokyo, Japan. This study was approved by the ethical committee in Toranomon Hospital. We performed immunohistochemical analysis with a polyclonal antibody against TRIM39. Immuno-stained slides were evaluated for intensity and proportion of nuclear staining. We examined the relationship between immunoreactivity of TRIM39 and clinico-pathological parameters and patients’ prognosis. In order to investigate TRIM39 biological function in breast cancer cells, we used MCF-7 and MDA-MB-231, breast cancer cell lines. We knocked down expression of TRIM39 and evaluated cell proliferation and cell migration. We investigated gene expression profiles affected by knockdown of TRIM39 with microarray analysis (Affymetrix, Clariom S). [Results] Among clinico-pathological parameters, higher pathological stage, higher pathological tumor size and higher nuclear grade were significantly associated with strong immunoreactivity of TRIM39. TRIM39 immunoreactivity was significantly associated with distant disease-free survival (p<0.001) and overall survival (p<0.001) of patients. Multivariate analysis revealed that the TRIM39 status was an independent prognostic factor for distant disease-free survival (p<0.001) and overall survival (p<0.001) of patients. Knockdown of TRIM39 markedly decreased proliferation of both cell lines and also inhibited migration of MDA-MB-231 cells. Microarray analysis and qRT-PCR revealed that TRIM39 knockdown downregulated CDCA3 and CDC25C in both cell lines. [Discussion] The present study suggested that strong expression of TRIM39 protein may be used as a prognostic biomarker for breast cancer patients. Moreover, TRIM39 would be a potential therapeutic target for breast cancer, considering TRIM39 knockdown caused attenuated proliferation and migration in breast cancer cells. CDCA3 and CDC25C were identified as genes regulated by TRIM39. CDCA3 was shown to promote proliferation by activating the NF-κB/cyclin D1 signaling pathway. CDC25C was reported to increase cell survival by suppressing apoptosis signal-regulating kinase 1(ASK1). Thus, these proteins could be involved in the role of TRIM39 in proliferation of breast cancer cells. [Conclusion] TRIM39 is a poor prognostic factor for breast cancer patients and would be a potential therapeutic target for breast cancer. Citation Format: Takuya Ogura, Kotaro Azuma, Junichiro Sato, Keiichi Kinowaki, Kazuhiro Ikeda, Hidetaka Kawabata, Satoshi Inoue. TRIM39 is a poor prognostic factor for breast cancer patients and promotes proliferation and migration of breast cancer cells [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-06-11.