Abstract P6-03-15: MCL-1 confers oncogenic role in breast cancer through modulating drug resistance and cancer stemness by targeting MRP1

Abstract

Abstract Background: Breast cancer is the most common malignant tumor and the leading killer in women. Chemotherapy is one of the most important treatments for breast cancer. However, development of chemotherapy resistance is the main reason for 20-30% of breast cancer patients getting metastasis and leading to death. MCL-1, the anti-apoptotic protein, is not clarified in conforing chemotherapy resistance of Breast cancer. This work is mainly to prove that MCL-1 is the role of chemotherapy resistance and stemness of Breast cancer.Methods: We used large gene panels to detect pathological sections of tumors in drug-resistant and sensitive patients. We validated protein profiling by IHC in a larger cohort of samples. We performed the function of MCL-1 by knockdown and overexpression in vitro and in vivo. Luciferase assay and CHIP assay were used to prove the regulatory network between MCL-1 and MRP1.Result: Here, we find that MCL-1 is highly expressed in drug-resistant breast cancer tissues than sensitive. Functional studies reveal that MCL-1 plays important role in drug resistant by regulating apoptosis in breast cancer cells. We identity that knockdown of MCL-1 enhances sensitivity and reduces stem cell of breast cancer in vitro and in vivo, while overexpression has the opposite effect. Furthermore, by down and up regulation MCL-1, we show that MCL-1 regulates the expression of MRP1 (ABCC1) in breast cancer cells. Finally, we demonstrate that MCL-1 regulates ABCC1 expression through binding to its specific promoter region and promoting its transcription levels.Conclusion: Our work highlight the role of MCL-1 in chemoresistance and stemness, suggesting it could be used as a new clinical marker for breast cancer with drug resistance.Keyword:MCL-1, Breast cancer, chemoresistance, stemness, MRP1. Funding: Guangdong Natural Science Foundation No. 2017A030313719;Foundation Project of Guangzhou University of Traditional Chinese Medicine, No. XKP2019002. Citation Format: Yuzhu Zhang, Junyan Huang, Fengjie Bie, Liping Ren, Qianjun Chen. MCL-1 confers oncogenic role in breast cancer through modulating drug resistance and cancer stemness by targeting MRP1 [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-03-15.