Song, Chaeun

Abstract Type 2 diabetes (T2D) female patients have a higher risk of being diagnosed and have worse survival for breast cancer compared to non-diabetic females. Although the relationship between these two female diseases has been reported, specific functional studies on which subtypes of breast cancer are affected and which genes are regulated by T2D are little known. Here, I found that Forkhead Box A1 (FOXA1) and Metformin, anti-diabetic medication for T2D, affect hormonal positive (HR+) breast cancer tumor cell growth and metastasis. 14 diabetes-related genes highly expressed in three HR+ breast cancer cell lines but not other breast cancer subtypes using a 53,805 gene database obtained from NCBI GEO. Among the diabetes-related genes, FOXA1, MTA3, PAK4, FGFR3, and KIF22 were highly expressed in HR+ breast cancer from 4,032 breast cancer patient tissue samples using the Breast Cancer Gene Expression Omnibus. Specifically, the high expression of FOXA1 correlated to a worse ER+/PR+ breast cancer patient survival rate. Consistent with this, the loss of FOXA1 inhibited the tumor proliferation and invasion of MCF-7 and T47D HR+ breast cancer cell lines using in vitro. Metformin (1,1-dimethylbiguanide hydrochloride) conspicuously inhibits the tumor cell growth in MCF-7 human hormonal breast cancer cells. Metformin or FOXA1 deletion enhanced Tamoxifen-mediated tumor growth inhibition in HR+ breast cancer cell lines through the ex vivo three-dimensional (3D) organoid model. Therefore, HR+ breast cancer is closely related to T2D, and metformin and FOXA1 inhibition might be an optimal new treatment for patients with HR+ breast cancer when combined with tamoxifen, a hormone therapy. Citation Format: Chaeun (Christine) Song, SeungBaek Lee. A novel approach to treating hormonal breast cancer using clinical database and 3D ex vivo model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1331.

Abstract The anti-estrogen tamoxifen is a highly effective hormonal therapy for hormonal (HR+) breast cancer patients. However, the estrogen receptor-negative, progesterone receptor-positive (ER-/PR+) subtype does not receive the benefits of tamoxifen. Therefore ER-/PR+ breast cancer have a poor clinical outcome, but drug development for ER-/PR+ breast cancer is not well studied. Here, we found that gene expression in ER-/PR+ HR+ breast cancer is positively related to triple negative breast cancer (TNBC) and not HR+ breast cancer using 4,319 breast cancer patients database. Especially, inflammation-related genes, A20/TNFAIP3, CDC20 and CASP1/Caspase-1, which are highly expressed in TNBC, are also upregulated in ER-/PR+ HR+ breast cancer. Suppression of A20/TNFAIP3, CDC20 and CASP1 inhibit cancer cell growth and metastasis in ERα KO (ER-/PR+) cell lines. Interestingly, loss of ERα in HR+ cell lines is not responsive to tamoxifen, but highly sensitive to inflammation inhibitor, Ac-YVAD-CHO. In in vitro and ex vivo models, inflammation inhibitor specifically blocks ER-/PR+ tumor proliferation and migration. These findings suggest that the inflammation inhibitor might be the first potential target therapy for ER-/PR+ HR breast cancer patients. Citation Format: Chaeun (Christine) Song, Val J. Lowe, SeungBaek Lee. Loss of inflammation-related genes and inflammation inhibitors effectively targets ER- breast cancer cell metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6210.

Abstract Cell division cycle 20 (Cdc20) is the main activator of the anaphase-promoting complex (APC/C) and is essential in mitosis regulation. Recently, several papers reported that Cdc20 is highly conserved in various human cancers such as pancreatic, prostate, and lung cancers yet its relation to breast cancer is unclear. Here, we found that Cdc20 gene was highly expressed in three different TNBC cell lines among the mitosis regulator genes through the National Center for Biotechnology Information (NCBI). High Cdc20 level is positively correlated with metastasis-free patient survival and relapse-free patient survival in breast cancer patient database. We also checked that Cdc20 is highly conserved in all TNBC cell lines compared to other subtypes of breast cancer cell lines and the knockdown of this gene decreased cell growth and invasion in TNBC. Furthermore, we investigated that the mitosis-related small molecule protein kinase inhibitors such as VX-680, ZM447439, BI2536, and apcin also inhibit tumor cell proliferation, migration, and invasion. In conclusion, Cdc20 has an important role in TNBC cell growth and metastasis. Cdc20 might serve as a potential marker of disease progression and as a principal potential therapeutic target. Also, mitosis-related protein kinase inhibitors are additional potential therapy to suppress cancer cell progression and invasion in TNBC effectively. Citation Format: Chaeun Song, SeungBaek Lee. Mitotic inhibitors suppresses tumor formation and metastasis of triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2890.