MCL-1 is a clinically targetable vulnerability in breast cancer

Winder, Matthew L.; Campbell, Kirsteen J.

doi:10.1080/15384101.2022.2054096

Cited by 15 publications

(9 citation statements)

References 136 publications

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“…Also, Mcl1, a survival factor from the Bcl2 family, might be a direct or indirect target of miR342. 14 Mcl1 inhibitors can boost the efficacy of conventional treatments since this molecule is highly expressed in breast cancer, 23 especially the triple-negative type is highly dependent on this protein. 24 Interestingly, Mcl1 overexpression in breast cancer is more common than that of Bcl2 and Bcl2l1.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory effect of miR342 on the progression of triple-negative breast cancer cells in vitro and in the mice model

Alidoost,

Attari,

Saadatpour

et al. 2023

Bioimpacts

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Introduction: Breast cancer is the most common cancer in women worldwide, and the triple-negative subtype is the most invasive, with limited therapeutic options. Since miRNAs are involved in many cellular processes, they harbor great value for cancer treatment. Therefore, in this study, we have investigated the anti-proliferative and anti-invasive roles of miR342 in 4T1 triple-negative cells in vitro and also studied the effect of this miRNA on tumor progression and the expression of its target genes in vivo. Methods: 4T1 cells were transduced with conditioned media of miR342-transfected Hek-LentiX cells. MTT and clonogenic assays were used to assess the viability and colony-forming ability of 4T1 cells. Apoptosis and invasion rates were respectively evaluated by annexin/7-AAD and wound healing assays. At last, in vivo tumor progression was evaluated using H&E staining, Real-time PCR, and immunohistochemistry. Results: The viability of transduced-4T1 cells reduced significantly 48 hours after cell seeding and colony forming ability of these cells reduced to 50% of the control group. Also, miR342 imposed apoptotic and anti-invasive influence on these cells in vitro. A 30-day follow-up of the breast tumor in the mice model certified significant growth suppression along with reduced mitotic index and tumor grade in the treatment group. Moreover, decreased expression of Bcl2l1, Mcl1, and ID4, as miR342 target genes, was observed, accompanied by reduced expression of VEGF and Bcl2/Bax ratio at the protein level. Conclusions: To conclude, our data support the idea that miR342 might be a potential therapeutic target for the treatment of TNBC.

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Section: Discussionmentioning

confidence: 99%

Inhibitory effect of miR342 on the progression of triple-negative breast cancer cells in vitro and in the mice model

Alidoost,

Attari,

Saadatpour

et al. 2023

Bioimpacts

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“…In particular, the Elk-1 bond at the SRE site of the EGR1 promoter was sufficient for EGF-mediated EGR1 expression ( Gregg and Fraizer, 2011 ; Yang et al ., 2020 ). In breast cancer cells, EGF-induced activation of Elk-1 contributed to cell survival through Mcl-1 regulation ( Booy et al ., 2011 ; Winder and Campbell, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

HPV-18 E7 Interacts with Elk-1 Leading to Elevation of the Transcriptional Activity of Elk-1 in Cervical Cancer

Rho

Yang

et al. 2022

Biomol Ther (Seoul)

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The human papillomavirus (HPV)-18 E7 (E7) oncoprotein is a major transforming protein that is thought to be involved in the development of cervical cancer. It is well-known that E7 stimulates tumour development by inactivating pRb. However, this alone cannot explain the various characteristics acquired by HPV infection. Therefore, we examined other molecules that could help explain the acquired cancer properties during E7-induced cancer development. Using the yeast two-hybrid (Y2H) method, we found that the Elk-1 factor, which is crucial for cell proliferation, invasion, cell survival, anti-apoptotic activity, and cancer development, binds to the E7. By determining which part of E7 binds to which domain of Elk-1 using the Y2H method, it was found that CR2 and CR3 of the E7 and parts 1–206, including the ETS-DNA domain of Elk-1, interact with each other. As a result of their interaction, the transcriptional activity of Elk-1 was increased, thereby increasing the expression of target genes EGR-1, c-fos, and E2F. Additionally, the colony forming assay revealed that overexpression of Elk-1 and E7 promotes C33A cell proliferation. We expect that the discovery of a novel E7 function as an Elk-1 activator could help explain whether the E7 has novel oncogenic activities in addition to p53 inactivation. We also expect that it will offer new methods for developing improved strategies for cervical cancer treatment.

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“…The PEST domain of Mcl-1 interacts with AKT on the PH domain, activating the AKT signal pathway and collectively promoting the progression of lung cancer . Research has also indicated that the abnormal increase in levels of Mcl-1 can lead to drug resistance in targeted therapy for BC. − BH3 mimetics that target Bcl-2/Bcl-xL in combination with docetaxel or tamoxifen show promise in the treatment of BC. However, tumor cells often become insensitive to this treatment due to the high expression of Mcl-1.…”

Section: Research Progress Of Modulators Targeting Mcl-1 In Cancer Tr...mentioning

confidence: 99%

Targeting Myeloid Leukemia-1 in Cancer Therapy: Advances and Directions

Deng,

Han,

Liu

et al. 2024

J. Med. Chem.

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As a tripartite cell death switch, B-cell lymphoma protein 2 (Bcl-2) family members precisely regulate the endogenous apoptosis pathway in response to various cell signal stresses through protein− protein interactions. Myeloid leukemia-1 (Mcl-1), a key anti-apoptotic Bcl-2 family member, is positioned downstream in the endogenous apoptotic pathway and plays a central role in regulating mitochondrial function. Mcl-1 is highly expressed in a variety of hematological malignancies and solid tumors, contributing to tumorigenesis, poor prognosis, and chemoresistance, making it an attractive target for cancer treatment. This Perspective aims to discuss the mechanism by which Mcl-1 regulates apoptosis and non-apoptotic functions in cancer cells and to outline the discovery and optimization process of potent Mcl-1 modulators. In addition, we summarize the structural characteristics of potent inhibitors that bind to Mcl-1 through multiple co-crystal structures and analyze the cardiotoxicity caused by current Mcl-1 inhibitors, providing prospects for rational targeting of Mcl-1. ■ SIGNIFICANCE • Pharmacological inhibition of protein−protein interactions between Mcl-1 and its substrates has become a promising approach to induce apoptotic or nonapoptotic functions in the treatment of various diseases. • Recent advancements in targeting Mcl-1 for tumor therapy are systematically summarized from medicinal chemistry insights. • The structural characteristics of potent inhibitors binding with Mcl-1 are analyzed. • The cardiotoxicity of Mcl-1 inhibitors is discussed, and structural modification strategies for future Mcl-1 inhibitors development are proposed.

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MCL-1 is a clinically targetable vulnerability in breast cancer

Cited by 15 publications

References 136 publications

Inhibitory effect of miR342 on the progression of triple-negative breast cancer cells in vitro and in the mice model

Inhibitory effect of miR342 on the progression of triple-negative breast cancer cells in vitro and in the mice model

HPV-18 E7 Interacts with Elk-1 Leading to Elevation of the Transcriptional Activity of Elk-1 in Cervical Cancer

Targeting Myeloid Leukemia-1 in Cancer Therapy: Advances and Directions

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