Abstract 4385: ZCCHC3 and Efp are prognostic factors for triple-negative breast cancer and potentially modulate cell division-related pathway

Abstract

Abstract Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with poor prognosis and limited therapeutic strategies, lacking expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. We previously demonstrated that estrogen responsive finger protein (Efp)/TRIM25 functions as a ubiquitin ligase that degrades cell cycle checkpoint 14-3-3 sigma and promotes cell growth of ER-positive breast cancer [Urano et al., Nature 417:871-875, 2002]. In TNBC cells, we further showed that Efp regulates cell cycle-related gene expression and promotes cell proliferation [Sato et al., Biochem Biophys Res Commun 624:81-88, 2022]. Efp also exerts a distinct function to activate cellular RNA sensors such as RIG-I (retinoic acid inducible gene I), which plays a role in the innate immunity [Gack et al., Nature 446:916-920, 2007]. Another immune-related gene zinc finger CCHC domain-containing protein 3 (ZCCHC3) was recently suggested as Efp interactor, although its pathological relevance in breast cancer remains elusive. We here aimed to clarify the role of ZCCHC3 in TNBC. Immunohistochemical analysis of TNBC tissues from over 100 Japanese patients showed that a positive ZCCHC3 immunoreactivity (IR) was significantly associated with shorter disease-free survival (DFS) and positively correlated with Efp IR. Notably, patients with both ZCCHC3 and Efp IR positivity showed much shorter DFS than those with ZCCHC3 positivity alone. Functional analysis of ZCCHC3 by siRNA silencing demonstrated that ZCCHC3 promotes the proliferation, migration, and cell cycle progression of MDA-MB-231 TNBC cells. We established long-term culturable TNBC patient-derived cells (TNBC-PDC) using spheroid culture technique and revealed that the spheroid growth was suppressed by ZCCHC3-specific siRNA treatment. Moreover, ZCCHC3-specific siRNA injection suppressed in vivo tumor growth of MDA-MB-231 cells inoculated in immunodeficient mice. RNA sequencing analysis of ZCCHC3-silenced TNBC cells showed that cell division-related pathway was enriched among downregulated genes, including non-structural maintenance of chromosomes condensin I complex subunit H (NCAPH). NCAPH silencing inhibited the proliferation of TNBC-PDCs and MDA-MB-231 cells. Overall, ZCCHC3 and Efp are potential poor prognostic factors and can be applied to alternative therapeutic options for TNBC. Citation Format: Akihiro Fujimoto, Kazuhiro Ikeda, Toshihiko Takeiwa, Keiichi Kinowaki, Takuya Ogura, Hidetaka Kawabata, Akihiko Osaki, Kuniko Horie, Satoshi Inoue. ZCCHC3 and Efp are prognostic factors for triple-negative breast cancer and potentially modulate cell division-related pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4385.