Abstract P2-26-19: Slc26a9 cooperates with HER2 to regulate the progression and development of HER2-positive breast cancer

Abstract

Abstract Goals: Ion transporters play an important regulatory role in the progression and development of breast cancer (BC). Slc26a9 is a member of the Slc26a anion transporter family, which is mainly involved in regulating the secretion of chloride ions and bicarbonate, but the role of Slc26a9 in HER2-positive BC is still unclear. Methods: Tissue microarray and BC cell line were used to detect the expression level of Slc26a9 and its clinical relevance. By changing the expression level of Slc26a9 gene in BC cells, the effect of Slc26a9 gene on the biological behavior of BC cells and its related molecular mechanism were discussed. Results: We found that the expression of Slc26a9 was significantly upregulated in BC compared with adjacent tissues, and the upregulated Slc26a9 was associated with TNM staging and poor prognosis in BC patients. In addition, the expression of Slc26a9 was significantly upregulated in HER2-positive BC compared with HER2-negative BC, and similar results were obtained in BC cell lines, with Slc26a9 was the highest expression in HER2-enriched SKBR3 cells. Functionally, the proliferation, migration, invasion and anti-apoptotic abilities of SKBR3 cells were significantly inhibited after silencing Slc26a9, and tumorigenesis and metastasis were significantly inhibited in vivo. On the contrary, overexpression of Slc26a9 resulted in the opposite result. Mechanistically, overexpression of Slc26a9 activated the PI3K/AKT/mTOR signaling pathway, the key signaling pathway implicated in HER2-positive breast carcinogenesis, and promoted the expression of downstream proliferation related genes CCND1 (Cyclin D1) and c-Myc, and downregulated the expression of apoptosis related genes Caspase9, apoptosis-inducing factor (AIF) and endonuclease G (Endo G), indicating the simultaneous inhibition of caspase dependent and independent apoptosis pathway. At the same time, accompanied by changes in markers of epithelial-mesenchymal transition (EMT), including downregulation of E-cadherin and ZO-1, and upregulation of N-cadherin and Fibronectin, and SKBR3 cells changed from epithelioid morphology to mesenchymal morphology. In addition, immunofluorescence and protein nucleoplasm separation experiments showed that Slc26a9 upregulated the expression of HER2 and co-localized with HER2 in the nucleus. Co-immunoprecipitation experiments proved that Slc26a9 interacted with HER2. Furthermore, trastuzumab downregulated the expression of Slc26a9 by targeting HER2 in SKBR3 cells. Moreover, when Slc26a9 was overexpressed, the inhibitory effect of trastuzumab on HER2 was partially reversed, and we also verified the PI3K/AKT/mTOR signaling pathway. Not only that, we found that Slc26a9 was significantly upregulated in drug-resistant cell lines relative to parental cells by constructing SKBR3 drug-resistant cell lines, indicating that Slc26a9 expression was significantly correlated with chemotherapy resistance in HER2-positive BC. Conclusion(s): Slc26a9 may interact with HER2 in the form of molecular chaperones to activate PI3K/AKT/mTOR signaling pathway to promote the progression and development of HER2-positive BC and be associated with chemotherapy resistance, but the precise molecular mechanism needs further exploration. Conflict of Interest: No significant relationships. Citation Format: Zhengxing Zhou, Zhiyuan Ma, Xuemei Liu, Chengmin Zhang, Hu Wang, Renmin Mu, Xiaoming Cheng, Biguang Tuo, Taolang Li. Slc26a9 cooperates with HER2 to regulate the progression and development of HER2-positive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-26-19.