MYC pathway activation in triple-negative breast cancer is synthetic lethal with CDK inhibition

Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 03/2012; 209(4):679-96. DOI: 10.1084/jem.20111512
Source: PubMed


Estrogen, progesterone, and HER2 receptor-negative triple-negative breast cancers encompass the most clinically challenging subtype for which targeted therapeutics are lacking. We find that triple-negative tumors exhibit elevated MYC expression, as well as altered expression of MYC regulatory genes, resulting in increased activity of the MYC pathway. In primary breast tumors, MYC signaling did not predict response to neoadjuvant chemotherapy but was associated with poor prognosis. We exploit the increased MYC expression found in triple-negative breast cancers by using a synthetic-lethal approach dependent on cyclin-dependent kinase (CDK) inhibition. CDK inhibition effectively induced tumor regression in triple-negative tumor xenografts. The proapoptotic BCL-2 family member BIM is up-regulated after CDK inhibition and contributes to this synthetic-lethal mechanism. These results indicate that aggressive breast tumors with elevated MYC are uniquely sensitive to CDK inhibitors.

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Available from: Paul Yaswen, Oct 02, 2015
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    • "The increased copy number of MCL1 was found in more than 10% of cancers, but the amplification was higher in lung and breast cancers [42]. Recent research progression of TNBC indicated that Myc and MCL1 are both upregulated in TNBC and they play important role in cell survival [43]. In the current study, we demonstrated that WNT5B-stimulated WNT/β-catenin signaling held MCL1 at high level via its target protein, Myc. "
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    ABSTRACT: Triple negative breast cancer (TNBC) has higher rates of recurrence and distant metastasis, and poorer outcome as compared to non-TNBC. Aberrant activation of WNT signaling has been detected in TNBC, which might be important for triggering oncogenic conversion of breast epithelial cell. Therefore, we directed our focus on identifying the WNT ligand and its underlying mechanism in TNBC cells. We performed large-scale analysis of public microarray data to screen the WNT ligands and the clinical significance of the responsible ligand in TNBC. WNT5B was identified and its overexpression in TNBC was confirmed by immunohistochemistry staining, Western blot and ELISA. ShRNA was used to knockdown WNT5B expression (shWNT5B). Cellular functional alteration with shWNT5B treatment was determined by using wound healing assay, mammosphere assay; while cell cycle and apoptosis were examined by flowcytometry. Mitochondrial morphology was photographed by electron microscope. Biological change of mitochondria was detected by RT-PCR and oxygen consumption assay. Activation of WNT pathway and its downstream targets were evaluated by liciferase assay, immunohistochemistry staining and immunoblot analysis. Statistical methods used in the experiments besides microarray analysis was two-tailed t-test. WNT5B was elevated both in the tumor and the patients' serum. Suppression of WNT5B remarkably impaired cell growth, migration and mammosphere formation. Additionally, G0/G1 cell cycle arrest and caspase-independent apoptosis was observed. Study of the possible mechanism indicated that these effects occurred through suppression of mitochondrial biogenesis, as evidenced by reduced mitochondrial DNA (MtDNA) and compromised oxidative phosphorylation (OXPHOS). In Vivo and in vitro data uncovered that WNT5B modulated mitochondrial physiology was mediated by MCL1, which was regulated by WNT/beta-catenin responsive gene, Myc. Clinic data analysis revealed that both WNT5B and MCL1 are associated with enhanced metastasis and decreased disease-free survival. All our findings suggested that WNT5B/MCL1 cascade is critical for TNBC and understanding its regulatory apparatus provided valuable insight into the pathogenesis of the tumor development and the guidance for targeting therapeutics.
    BMC Cancer 02/2014; 14(1):124. DOI:10.1186/1471-2407-14-124 · 3.36 Impact Factor
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    • "Previous studies showed that up-regulation of BIM expression was required for MYC overexpression-induced apoptosis [58] and contributed to cell death induced by the CDK inhibitor purvalanol A in breast cancer cells [46]. Consistent with these studies, we found that CDK1 inhibitors induced BIM expression and that elevated BIM expression was associated with increased sensitivity to CDK1 inhibitors in cells with high MYC expression. "
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    ABSTRACT: Although MYC is an attractive therapeutic target for breast cancer treatment, it has proven challenging to inhibit MYC directly, and clinically effective pharmaceutical agents targeting MYC are not yet available. An alternative approach is to identify genes that are synthetically lethal in MYC-dependent cancer. Recent studies have identified several cell cycle kinases as MYC synthetic-lethal genes. We therefore investigated the therapeutic potential of specific cyclin-dependent kinase (CDK) inhibition in MYC-driven breast cancer. Using small interfering RNA (siRNA), MYC expression was depleted in 26 human breast cancer cell lines and cell proliferation evaluated by BrdU incorporation. MYC-dependent and MYC-independent cell lines were classified based on their sensitivity to siRNA-mediated MYC knockdown. We then inhibited CDKs including CDK4/6, CDK2 and CDK1 individually using either RNAi or small molecule inhibitors, and compared sensitivity to CDK inhibition with MYC dependence in breast cancer cells. Breast cancer cells displayed a wide range of sensitivity to siRNA-mediated MYC knockdown. The sensitivity was correlated with MYC protein expression and MYC phosphorylation level. Sensitivity to siRNA-mediated MYC knockdown did not parallel sensitivity to the CDK4/6 inhibitor PD0332991; instead MYC-independent cell lines were generally sensitive to PD0332991. Cell cycle arrest induced by MYC knockdown was accompanied by a decrease in CDK2 activity, but inactivation of CDK2 did not selectively affect the viability of MYC-dependent breast cancer cells. In contrast, CDK1 inactivation significantly induced apoptosis and reduced viability of MYC-dependent cells but not MYC- independent cells. This selective induction of apoptosis by CDK1 inhibitors was associated with up-regulation of the pro-apoptotic molecule BIM and was p53-independent. Overall, these results suggest that further investigation of CDK1 inhibition as a potential therapy for MYC-dependent breast cancer is warranted.
    BMC Cancer 01/2014; 14(1):32. DOI:10.1186/1471-2407-14-32 · 3.36 Impact Factor
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    • "Pathway analysis [21] of the mutation data identified several cell signaling networks associated with anti-proliferative response to an AI, such as the MAPK, FYN (an Src-family kinase), and MYC pathways. Both the MYC and MAPK pathways have been reported to be highly activated in (ER−) basal-like tumors and cell lines [22,23]. Finally, the authors also reported mutations in the HER2 gene in the absence of gene amplification. "
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    ABSTRACT: Recent advances in whole-genome technologies have supplied the field of cancer research with an overwhelming amount of molecular data. Improvements in massively parallel sequencing approaches have led to logarithmic decreases in costs, and so these methods are becoming almost commonplace in the analysis of clinical trials and other cohorts of interest. Furthermore, whole-transcriptome quantification by RNA sequencing is quickly replacing microarrays. However, older chip-based methodologies such as comparative genomic hybridization and single-nucleotide polymorphism arrays have benefited from this technological explosion and are now so accessible that they can be employed in increasingly larger cohorts of patients. The study of breast cancer lends itself particularly well to these technologies. It is the most commonly diagnosed neoplasm in women, giving rise to nearly 230,000 new cases each year. Many patients are given a diagnosis of early-stage disease, for which surgery is the standard of care. These attributes result in excellent availability of tissues for whole-genome/transcriptome analysis. The Cancer Genome Atlas project has generated comprehensive catalogs of publically available genomic breast cancer data. In addition, other studies employing the power of genomic technologies in medium to large cohorts were recently published. These data are now publically available for the generation of novel hypotheses. However, these studies differed in the methods, patient cohorts, and analytical techniques employed and represent complementary snapshots of the molecular underpinnings of breast cancer. Here, we will discuss the convergences and divergences of these reports as well as the scientific and clinical implications of their findings.
    Breast cancer research: BCR 07/2013; 15(4):209. DOI:10.1186/bcr3435 · 5.49 Impact Factor
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