Lee, SeungBaek

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 Mutations in the E3 ubiquitin ligase Parkin have been linked to familial Parkinson’s disease as well as various human cancers. Although the activation of Parkin's E3 ligase is well characterized, the mechanism that tunes down tumorigenesis by phosphorylation-mediated auto-ubiquitination is largely unknown. Here we found that Parkin S378 is phosphorylated in mitosis while Parkin S131 is phosphorylated in late G1-S. Parkin protein levels were significantly lower in interphase compared to mitosis. Also, we checked that parkin itself degraded the protein by autoubiquitination in the cells overexpressing Parkin S131. Parkin S131D mutant significantly increased the rate of tumorigenesis compared to the control in in vitro and mouse models. Furthermore, Parkin S131 mutation was found in several patients with prostate cancer. These results suggest that the inactivation of Parkin by auto-ubiquitination impairs its ubiquitination activity and abolishes its tumor-suppressive effect in prostate cancer. Citation Format: SeungBaek Lee. Loss of Parkin's inactivation by autoubiquitination induces prostate cancer tumorigenesis [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 824.

Extracellular matrix stiffness controls DNA damage response.

Abstract Elucidating mechanisms of chemoresistance is critical to improve cancer therapy, especially for the treatment of pancreatic ductal adenocarcinoma (PDAC). Genome-wide association studies have suggested the less studied gene HEAT repeat-containing protein 1 (HEATR1) as a possible determinant of cellular sensitivity to different chemotherapeutic drugs. In this study, we assessed this hypothesized link in PDAC, where HEATR1 expression is downregulated significantly. HEATR1 silencing in PDAC cells increased resistance to gemcitabine and other chemotherapeutics, where this effect was associated with increased AKT kinase phosphorylation at the Thr308 regulatory site. Mechanistically, HEATR1 enhanced cell responsiveness to gemcitabine by acting as a scaffold to facilitate interactions between AKT and the protein phosphatase PP2A, thereby promoting Thr308 dephosphorylation. Consistent with these findings, treatment with the AKT inhibitor triciribine sensitized HEATR1-depleted PDAC cells to gemcitabine, suggesting that this therapeutic combination may overcome gemcitabine resistance in patients with low HEATR1 expression. Clinically, we found that HEATR1 downregulation in PDAC patients was associated with increased AKT phosphorylation, poor response to tumor resection plus gemcitabine standard-of-care treatment, and shorter overall survival. Collectively, our findings establish HEATR1 as a novel regulator of AKT and a candidate predictive and prognostic indicator of drug responsiveness and outcome in PDAC patients. Cancer Res; 76(3); 572–81. ©2015 AACR.