Abstract 1635: Targeting ferroptosis in CCDC88A-overexpressing metastatic triple-negative breast cancer

Abstract Triple-negative breast cancer (TNBC) is a form of breast cancer that does not express estrogen receptor (ER), progesterone receptors (PR) or human epidermal growth factor receptor 2 (HER2). It accounts for 15-20% of all breast carcinomas and preferentially affects women who are African American, younger than age 40, or have a BRCA1 mutation. The TNBC subtype is highly aggressive and heterogeneous and has a poor prognosis relative to other breast cancer subtypes due to a lack of highly recurrent and actionable biomarkers that can be used to direct therapy. Although standard chemotherapies show a high initial response rate in TNBC, tumor relapses and metastasis often occur rapidly. Moreover, for patients who have recurrent disease or progressive disease during chemotherapy, treatment options are limited. Therefore, there is an unmet need to identify effective therapies targeting TNBC. By analyzing public human datasets, we found that CCDC88A (also known as Girdin or GIV), a putative oncogene, is highly expressed in TNBC compared to other breast cancer subtypes. CCDC88A has been found to be involved in key cancer development events such as tumor angiogenesis, invasion, wound healing, and metastasis. Interestingly, we found that, although the high expression of CCDC88A conferred the ability of lung metastasis, it increased the susceptibility of TNBC to ferroptosis, a type of cell death induced by iron-dependent lipid peroxidation. Mechanistically, CCDC88A sensitized TNBC cells to ferroptosis by limiting intracellular glutathione (GSH) levels. shRNA-mediated CCDC88A knockdown in TNBC cells significantly increased GSH levels and in turn blunted cellular sensitivity to ferroptosis. On the other hand, inhibition of GSH synthesis with a glutamate-cysteine ligase (GCL) inhibitor, BSO, restored the ferroptosis sensitivity in CCDC88A knocked-down TNBC cells. Thus, our findings uncover CCDC88A as a novel ferroptosis regulator and also suggest that ferroptosis is a therapeutically tractable target for metastatic TNBC that overexpresses CCDC88A. Citation Format: Wei-Ling Tu, Mu-En Wang, Ji-Hoon Kim, Alyssa Bawcom, Yi Lu, Ming Chen. Targeting ferroptosis in CCDC88A-overexpressing metastatic triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1635.