MCL-1 plays an oncogenic role in breast cancer by modulating chemoresistance and stemness properties by activating Wnt/β-catenin

Abstract

Background Breast cancer is the most common malignant tumor and the leading cause of death in women. Chemotherapy is one of the most important treatments for breast cancer. However, the development of chemotherapy resistance is the main cause of 20–30% of breast cancer patients developing metastasis, leading to death. MCL-1, an anti-apoptotic protein, has not been found to contribute to chemotherapy resistance in 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 LRP6. Result We found that MCL-1 is more highly expressed in drug-resistant breast cancer tissues than it is in sensitive breast cancer tissues. Functional studies have revealed that MCL-1 plays an important role in drug resistance by regulating apoptosis in breast cancer cells. We found that overexpression of MCL-1 enhances the chemoresistance and stemness of breast cancer cells in vitro and in vivo, while silencing has the opposite effect. Mechanistically, by downregulating and upregulating MCL-1, we show that MCL-1 regulates LRP6 and activates the WNT/β-catenin signaling pathway in breast cancer cells. Finally, we found that a high level of MCL-1 expression predicts a poor prognosis in breast cancer. Conclusion Our work highlights the role of MCL-1 in chemoresistance and stemness. The MCL-1-WNT/β-catenin axis might be used as a new clinical target for breast cancer therapy.

Characterization of BCL-XL, MCL-1, and BAX Protein Expression in Response to Neoadjuvant Chemotherapy in Breast Cancer

“…Moreover, MCL-1 expression can be considered a prognostic biomarker that may help assess the efficacy of chemotherapy (that is, response to chemotherapy) and its effect on inducing apoptosis. In fact, previous studies confirmed that overexpression of MCL-1 is closely associated with poor prognosis and poor outcome 45,62–64 . Interestingly, Lee et al showed that in a distinct immunohistochemical subtype of breast cancer patients, TNBC, resistance to chemotherapy develops as a consequence of the failure to induce a downregulation in MCL-1 expression 65 .…”

“…In fact, previous studies confirmed that overexpression of MCL-1 is closely associated with poor prognosis and poor outcome. 45,[62][63][64] Interestingly, Lee et al showed that in a distinct immunohistochemical subtype of breast cancer patients, TNBC, resistance to chemotherapy develops as a consequence of the failure to induce a downregulation in MCL-1 expression. 65 In addition, Eustace et al reported that patients treated with lapatinib, an EGFR inhibitor, are more likely to have elevated MCL-1 levels.…”

Illuminating the role of lncRNAs ROR and MALAT1 in cancer stemness state of anaplastic thyroid cancer: An exploratory study

“…The human stem cell hierarchy has a functional dependence on MCL1 for self-renewal capability [ 14 ]. Over-expression of MCL1 in breast cancer cells increased stemness features and resistance to chemotherapy while its inhibition had the opposite effect [ 31 ]. MALAT1 indirectly affects the expression of its downstream related genes through its interplay with mediators such as miRNAs [ 32 ].…”