MCL-1 is a prognostic indicator and drug target in breast cancer

Campbell, Kirsteen J.; Dhayade, Sandeep; Ferrari, Nicola; Sims, Andrew H.; Johnson, Emma; Mason, Susan; Dickson, Ashley; Ryan, Kevin M.; Kalna, Gabriela; Edwards, Joanne; Tait, Stephen W.G.; Blyth, Karen

doi:10.1038/s41419-017-0035-2

Cited by 164 publications

(166 citation statements)

References 56 publications

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“…Experimental validation in a panel of breast cancer cell lines coupled with genomic analyses in large patient cohorts identified the MCL1 level as a predictor for response to combined inhibition of MCL1 and BETis. MCL1 amplification is a well-characterized prognostic factor in breast cancer (12,33). Here we showed that MCL1i were effective in cells with MCL1 gain or amplification and that breast cancer cells are further sensitized to MCL1 inhibition when combined with BETis.…”

Section: Discussionmentioning

confidence: 73%

“…With the introduction of specific inhibitors, MCL1 has become an actionable therapeutic target. Broader impact of MCL1 inhibitors could be achieved by selectively inducing survival dependencies that make use of higher levels of MCL1 (11)(12). For example, targeted agents that can generate therapeutic stress and MCL1-driven anti-apoptotic dependence may induce a clinically relevant vulnerability even in cases that carry low-level MCL1 gains.…”

Section: Introductionmentioning

confidence: 99%

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Adaptive response to BET inhibition induces therapeutic vulnerability to MCL1 inhibitors in breast cancer

Yan

Wang

Luna

et al. 2019

Preprint

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The development of effective targeted therapies for the treatment of basal-like breast cancers remains challenging. Here, we demonstrate that BET inhibition induces a multi-faceted adaptive response program leading to MCL1 protein-driven evasion of apoptosis in breast cancers. Consequently, co-targeting MCL1 and BET is highly synergistic in in vitro and in vivo breast cancer models. Drug response and genomics analyses revealed that MCL1 copy number alterations, including low-level gains, are selectively enriched in basal-like breast cancers and associated with effective BET and MCL1 co-targeting. The mechanism of adaptive response to BET inhibition involves upregulation of critical lipid metabolism enzymes including the rate-limiting enzyme stearoyl-CoA desaturase (SCD). Changes in the lipid metabolism are associated with increases in cell motility and membrane fluidity as well as transitions in cell morphology and adhesion. The structural changes in the cell membrane leads to re-localization and activation of HER2/EGFR which can be interdicted by inhibiting SCD activity. Active HER2/EGFR, in turn, induces accumulation of MCL1 protein and therapeutic vulnerability to MCL1 inhibitors. The BET protein, lipid metabolism and receptor tyrosine kinase activation cascade is observed in patient cohorts of basal-like and HER2-amplified breast cancers. The high frequency of MCL1 chromosomal amplifications (>30%) and gains (>50%) in basal-like breast cancers suggests that BET and MCL1 co-inhibition may have therapeutic utility in this aggressive subtype.

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Section: Discussionmentioning

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Adaptive response to BET inhibition induces therapeutic vulnerability to MCL1 inhibitors in breast cancer

Yan

Wang

Luna

et al. 2019

Preprint

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“…MCL1 gene is one of the B‐cell lymphoma 2 (BCL‐2) family, which monitors and regulates cell apoptosis. Failure to initiate apoptosis promotes the development of tumors and prevents cancer therapy‐induced cell death . BCL‐2 family comprises antiapoptotic and protoapoptotic members.…”

Section: Introductionmentioning

confidence: 91%

“…Failure to initiate apoptosis promotes the development of tumors and prevents cancer therapy-induced cell death. 11 BCL-2 family comprises antiapoptotic and protoapoptotic members. The overexpression of the antiapoptotic members of the BCL-2 family is a major proliferative factor of OVC cells.…”

Section: Introductionmentioning

confidence: 99%

miR‐153‐3p regulates progression of ovarian carcinoma in vitro and in vivo by targeting MCL1 gene

Cui

Zhang

Zhao

et al. 2019

J of Cellular Biochemistry

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The study of either miR‐153‐3p or MCL1 gene in ovarian carcinoma (OVC) has been reported; however, the interaction between miR‐153‐3p and MCL1 gene in OVC as well as the influence of their interaction on OVC progression has not been reported yet. Herein we intended to study the effects of miR‐153‐3p/MCL1 axis in OVC. Web‐based bioinformatics algorithms including DIANA TarBase 8.0, PicTar, and TargetScan Human 7.2 were used to predict the microRNAs (miRNAs) that could target MCL1 mRNA. Patient characteristics data collection and tissue sample immunohistochemical staining were used to determine the expression level of miR‐153‐3p and MCL1. We determined to unravel the effects of the pairing‐up of miR‐153‐3p and MCL1 mRNA in OVC cell lines (OVCAR3 cell line and A2780) and xenografts (immunodeficient(immunodeficient Rag−/− mice) using several methods including real‐time quantitative reverse transcription polymerase chain reaction, westernWestern blot, colony formation assay, wound healing assay, Transwell invasion assay, flow cytometry assay, and xenograft assay. These experiments were performed to study OVC cellular activities such as cell growth and death and so forth in vitro and in vivo. Plenty of miRNAs that can target MCL1 mRNA have been identified, and we have narrowed them down to miR‐153‐3p. MCL1 gene was found overexpressed in OVC tissues and OVC cell lines at RNA and protein levels, whereas miR‐153‐3p was found under‐expressed in OVC tissues and cells. miR‐153‐3p was found to target MCL1 mRNA and interfered OVC progression. The repression of MCL1 gene expression caused by either miR‐153‐3p or small interfering RNA technique led to significantly reduced OVC cell growth and invasion in vitro. Lastly, the engraftment of transfected human OVC cells into Rag−/− mice confirmed the in vitro results. MCL1 gene acts as a cancer facilitator in OVC. In this study, we revealed the role of miR‐153‐3p on OVC progression by targeting MCL1 gene. Our work could comprehend the current understanding of OVC progression and contribute to the underlying aggression mechanism of this cancer.

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“…Mcl-1 is an anti-apoptotic member of the Bcl-2 family proteins which is frequently upregulated in cancers to promote cell survival [96–99]. Under normal conditions, Mcl-1 associates with the proapoptotic BAK protein to maintain BAK in an inactive state whereas downregulation of Mcl-1 proteins is triggered by DNA damage, such as infection by viruses [100].…”

Section: Substrates Of Huwe1mentioning

confidence: 99%

Ubiquitination by HUWE1 in tumorigenesis and beyond

Kao

2018

J Biomed Sci

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Ubiquitination modulates a large repertoire of cellular functions and thus, dysregulation of the ubiquitin system results in multiple human diseases, including cancer. Ubiquitination requires an E3 ligase, which is responsible for substrate recognition and conferring specificity to ubiquitination. HUWE1 is a multifaceted HECT domain-containing ubiquitin E3 ligase, which catalyzes both mono-ubiquitination and K6-, K48- and K63-linked poly-ubiquitination of its substrates. Many of the substrates of HUWE1 play a crucial role in maintaining the homeostasis of cellular development. Not surprisingly, dysregulation of HUWE1 is associated with tumorigenesis and metastasis. HUWE1 is frequently overexpressed in solid tumors, but can be downregulated in brain tumors, suggesting that HUWE1 may possess differing cell-specific functions depending on the downstream targets of HUWE1. This review introduces some important discoveries of the HUWE1 substrates, including those controlling proliferation and differentiation, apoptosis, DNA repair, and responses to stress. In addition, we review the signaling pathways HUWE1 participates in and obstacles to the identification of HUWE1 substrates. We also discuss up-to-date potential therapeutic designs using small molecules or ubiquitin variants (UbV) against the HUWE1 activity. These molecular advances provide a translational platform for future bench-to-bed studies. HUWE1 is a critical ubiquitination modulator during the tumor progression and may serve as a possible therapeutic target for cancer treatment.

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MCL-1 is a prognostic indicator and drug target in breast cancer

Cited by 164 publications

References 56 publications

Adaptive response to BET inhibition induces therapeutic vulnerability to MCL1 inhibitors in breast cancer

Adaptive response to BET inhibition induces therapeutic vulnerability to MCL1 inhibitors in breast cancer

miR‐153‐3p regulates progression of ovarian carcinoma in vitro and in vivo by targeting MCL1 gene

Ubiquitination by HUWE1 in tumorigenesis and beyond

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