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

Horiuchi, Dai; Kusdra, Leonard; Huskey, Noelle E.; Chandriani, Sanjay; Lenburg, Marc E.; González-Angulo, Ana M.; Creasman, Katelyn J.; Bazarov, Alexey V.; Smyth, J. D.; Davis, Sarah E.; Yaswen, Paul; Mills, Gordon B.; Esserman, Laura J.; Goga, Andrei

doi:10.1084/jem.20111512

Cited by 314 publications

(289 citation statements)

References 78 publications

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“…MTBP protein levels were elevated in all of the TNBC cells (Fig 2C). In comparison, the oncogenic transcription factor MYC, which has previously been shown to positively regulate MTBP expression and to be elevated in aggressive breast cancers, was also elevated in these same cells (12, 24). Therefore, MTBP mRNA levels are the highest in patient samples of the clinically aggressive TNBC subtype, and TNBC cell lines have high levels of MTBP mRNA and protein.…”

Section: Resultsmentioning

confidence: 74%

“…TNBCs are reported to have a higher proliferative index when compared to receptor positive high-grade invasive carcinomas (29). In addition, elevated MYC transcriptional activity, which is correlated with decreased breast cancer patient survival, is linked to increased proliferation in breast cancer, and the TNBC subtype has the highest MYC transcriptional activity (24). We recently determined patients with breast cancers that express high levels of both MYC and MTBP have a worse prognosis than those with just high MYC expression (13), suggesting cooperation between MYC and MTBP overexpression in breast cancer.…”

Section: Discussionmentioning

confidence: 99%

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MTBP Is Overexpressed in Triple-Negative Breast Cancer and Contributes to Its Growth and Survival

Grieb

Chen

Eischen

2014

Molecular Cancer Research

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Triple negative breast cancer (TNBC) is a clinically aggressive subtype of breast cancer commonly resistant to therapeutics that have been successful in increasing survival in ER+ and HER2+ breast cancer patients. As such, identifying factors that contribute to poor patient outcomes and mediate the growth and survival of TNBC cells remain important areas of investigation. MTBP (MDM2 Binding Protein), a gene linked to cellular proliferation and a transcriptional target of the MYC oncogene, is over-expressed in human malignancies, yet its contribution to cancer remains unresolved. Evaluation of mRNA expression and copy number variation data from The Cancer Genome Atlas (TCGA) revealed MTBP is commonly over-expressed in breast cancer and 19% show amplification of MTBP. Increased transcript or gene amplification of MTBP significantly correlated with reduced breast cancer patient survival. Further analysis revealed that while MTBP mRNA is over-expressed in both ER+ and HER2+ breast cancers, its expression is highest in TNBC. MTBP mRNA and protein levels were also significantly elevated in a panel of human TNBC cell lines. Knockdown of MTBP in TNBC model systems induced apoptosis and significantly reduced TNBC cell growth and soft agar colony formation, which was rescued by expression of shRNA-resistant Mtbp. Notably, inducible knockdown of MTBP expression significantly impaired TNBC tumor growth, in vivo, including in established tumors. Thus, these data emphasize MTBP is important for the growth and survival of TNBC and warrants further investigation as a potential novel therapeutic target. Implications: MTBP significantly contributes to breast cancer survival and is a potential novel therapeutic target in TNBC.

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Section: Resultsmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

MTBP Is Overexpressed in Triple-Negative Breast Cancer and Contributes to Its Growth and Survival

Grieb

Chen

Eischen

2014

Molecular Cancer Research

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“…In addition, recent studies show that cell cycle regulation is an attractive target in cancer therapy, especially in gliomas [29, 30]. Cell cycle arrest triggers tumour senescence and prevents tumour progression and have not any obvious effects on normal tissues, which may be related to the inhibition of regulators such as CDK1, D-type cyclins, CDK4 and CDK6[31, 32]. Our data showed that isogambogenic acid led to cell cycle arrest in human glioma U87 and U251 cells, so this drug has a good toxicity against gliomas and may have a low toxicity in normal tissues.…”

Section: Discussionmentioning

confidence: 99%

Isogambogenic Acid Inhibits the Growth of Glioma Through Activation of the AMPK-mTOR Pathway

Zhao

Peng

Shu

et al. 2017

Cell Physiol Biochem

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Background/Aims: Glioma is the most devastating cancer in the brain and has a poor prognosis in adults. Therefore, there is a critical need for novel therapeutic strategies for the management of glioma patients. Isogambogenic acid, an active compound extracted from the Chinese herb Garcinia hanburyi, induces autophagic cell death. Methods: Cell viability was detected with MTT assays. Cell proliferation was assessed using the colony formation assay. Morphological changes associated with autophagy and apoptosis were tested by TEM and Hoechst staining, respectively. The apoptosis rate was measured by flow cytometry. Western blot, immunofluorescence and immunohistochemical analyses were used to detect protein expression. U87-derived xenografts were established for the examination of the effect of isogambogenic acid on glioma growth in vivo. Results: Isogambogenic acid induced autophagic death in U87 and U251 cells, and blocking late-stage autophagy markedly enhanced the antiproliferative activities of isogambogenic acid. Moreover, we observed the activation of AMPK-mTOR signalling in isogambogenic acid-treated glioma cells. Furthermore, the activation of AMPK or the inhibition of mTOR augmented isogambogenic acid-induced autophagy. Inhibition of autophagy attenuated apoptosis in isogambogenic acid-treated glioma cells. Finally, isogambogenic acid inhibited the growth of U87 glioma in vivo. Conclusion: Isogambogenic acid inhibits the growth of glioma via activation of the AMPK-mTOR signalling pathway, which may provide evidence for future clinical applications in glioma therapy.

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“…Even in the absence of level I evidence, the matching of patients to clinical trials of drugs that are likely to target each patient’s specific tumor’s molecular aberrations holds significant promise. Moreover, alterations that we did not consider actionable in this analysis may be sensitive to certain targeted therapeutics (eg, MYC and CDK inhibitors), and novel therapies directed at other targets such as TP53 are rapidly evolving (20). …”

Section: Discussionmentioning

confidence: 99%

Concordance of Genomic Alterations between Primary and Recurrent Breast Cancer

Meric‐Bernstam

Frampton²,

Ferrer-Lozano³

et al. 2014

Molecular Cancer Therapeutics

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104

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There is growing interest in delivering genomically-informed cancer therapy. Our aim was to determine the concordance of genomic alterations between primary and recurrent breast cancer. Targeted next generation sequencing was performed on formalin-fixed paraffin embedded (FFPE) samples, profiling 3320 exons of 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer. Point mutations, indels, copy number alterations and select rearrangements were assessed in 74 tumors from 43 patients (36 primary, 38 recurrence/metastases). Alterations potentially targetable with established or investigational therapeutics were considered “actionable”. Alterations were detected in 55 genes (mean 3.95 alterations/sample, range 1-12), including mutations in PIK3CA, TP53, ARID1A, PTEN, AKT1, NF1, FBXW7 and FGFR3 and amplifications in MCL1, CCND1, FGFR1, MYC, IGF1R, MDM2, MDM4, AKT3, CDK4, AKT2. In 33 matched primary and recurrent tumors, 97 of 112 (86.6%) somatic mutations were concordant. Of identified copy number alterations, 136 of 159 (85.5%) were concordant: 37 (23.3%) were concordant, but below the reporting threshold in one of the matched samples, and 23 (14.5%) discordant. There was an increased frequency of CDK4/MDM2 amplifications in recurrences, as well as gains and losses of other actionable alterations. 40 of 43 (93%) patients had actionable alterations that could inform targeted treatment options. In conclusion, deep genomic profiling of cancer-related genes reveals potentially actionable alterations in most breast cancer patients. Overall there was high concordance between primary and recurrent tumors. Analysis of recurrent tumors prior to treatment may provide additional insights, as both gains and losses of targets are observed.

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

Abstract: Triple-negative breast cancers with elevated MYC are sensitized to CDK inhibition.

Cited by 314 publications

References 78 publications

MTBP Is Overexpressed in Triple-Negative Breast Cancer and Contributes to Its Growth and Survival

MTBP Is Overexpressed in Triple-Negative Breast Cancer and Contributes to Its Growth and Survival

Isogambogenic Acid Inhibits the Growth of Glioma Through Activation of the AMPK-mTOR Pathway

Concordance of Genomic Alterations between Primary and Recurrent Breast Cancer

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