MYC and Metastasis

Wolfer, Anita; Ramaswamy, Sridhar

doi:10.1158/0008-5472.can-10-3776

Cited by 158 publications

(129 citation statements)

References 39 publications

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“…The oncogene c-Myc enhances protein translation through transactivating diverse targets, such as initiation factors, ribosomal proteins, and rRNAs. Activation of c-Myc is found in a variety of cancers, including breast cancer, and its activation seems to be a surrogate marker for cancers (44)(45)(46)(47)(48)(49). The role of c-Myc in driving protein synthesis is in part attributed to promoting ribosome production through transcribing a number of ribosomal proteins (34)(35)(36).…”

Section: Discussionmentioning

confidence: 99%

HSPC111 Governs Breast Cancer Growth by Regulating Ribosomal Biogenesis

Zhang

Yin

Wang

et al. 2014

Molecular Cancer Research

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Activation of c-Myc plays a decisive role in the development of many human cancers. As a transcription factor, cMyc facilitates cell growth and proliferation by directly transcribing a multitude of targets, including rRNAs and ribosome proteins. However, how to elucidate the deregulation of rRNAs and ribosome proteins driven by c-Myc in cancer remains a significant challenge and thus warrants close investigation. In this report, a crucial role for the HSPC111 (NOP16) multiprotein complex in governing ribosomal biogenesis and tumor growth was determined. It was discovered that enhanced HSPC111 expression paralleled the upregulation of c-Myc and was directly regulated by c-Myc in breast cancer cells. Knockdown of HSPC111 dramatically reduced the occurrence of tumorigenesis in vivo, and largely restrained tumor cell growth in vitro and in vivo. In stark contrast, HSPC111 overexpression significantly promoted tumor cell growth. Biochemically, it was demonstrated that RNA 3 0 -phosphate cyclase (RTCD1/RTCA) interacted with HSPC111, and RTCD1 was involved in the HSPC111 multiprotein complex in regulating rRNA production and ribosomal biogenesis. Moreover, HSPC111 and RTCD1 synergistically modulated cell growth and cellular size through commanding rRNA synthesis and ribosome assembly coupled to protein production. Finally, overall survival analysis revealed that concomitant upregulation of HSPC111 and RTCD1 correlated with the worst prognosis in a breast cancer cohort.Implications: Inhibition of HSPC111-dependent ribosomal biosynthesis and protein synthesis is a promising therapeutic strategy to diminish breast cancer tumor progression. Mol Cancer Res; 12(4); 583-94. Ó2014 AACR. IntroductionBreast cancer is by far the most common cancer among women and the leading cause of cancer-related deaths worldwide. The primary tumor and metastases to distant organs often cause significant morbidity and mortality. Numerous studies suggest that the oncogene c-Myc plays a crucial role in the development and progression of breast cancer. Along with its partner protein Max, c-Myc regulates an estimated 10% to 15% of genes in the human genome, and globally reprograms cells and drives proliferation (1-3). Aberrant regulation and overexpression of c-Myc are observed in most tumor types,

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Section: Discussionmentioning

confidence: 99%

HSPC111 Governs Breast Cancer Growth by Regulating Ribosomal Biogenesis

Zhang

Yin

Wang

et al. 2014

Molecular Cancer Research

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“…The c-Myc transcription factor is one of the most important somatically mutated oncogenes in human cancer and confers a selective advantage to cancer cells by promoting protein synthesis, proliferation, cell survival, differentiation, genetic instability, angiogenesis, hypoxia-mediated cancer progression, and metastasis (33,33,47,(62)(63)(64)(65)(66). Studies have shown that c-Myc up-regulates both eIF4E and eIF4G gene expression (58).…”

Section: Discussionmentioning

confidence: 99%

The Soy Isoflavone Equol May Increase Cancer Malignancy via Up-regulation of Eukaryotic Protein Synthesis Initiation Factor eIF4G

Parra

Otero-Franqui

Martínez-Montemayor

et al. 2012

Journal of Biological Chemistry

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Background: The molecular mechanisms of soy isoflavones in metastatic cancer remain to be elucidated. Results: Equol, a daidzein metabolite, regulates eIF4G-mediated cap-independent protein synthesis initiation of proteins relevant for cancer malignancy. Conclusion: Equol is a potent regulator of the cancer promoting effects of dietary daidzein. Significance: Consumption of soy may not be advisable for patients with aggressive breast cancer.

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“…[44][45][46][47][48][49][50][51][52][53][54][55] Both OSM/STAT3-and TGFb-induced senescence require the repression of MYC. 40,[56][57][58][59] Our lab has previously demonstrated that the expression of MYC from a constitutive promoter prevents OSM-or RAS-induced senescence and alters the response of HMEC to persistent oncogenic stimuli, from growth suppressive to growth promoting.…”

Section: Persistent Osm/stat3 Signaling Promotes Smad Targetgene Tranmentioning

confidence: 99%

STAT3-mediated SMAD3 activation underlies Oncostatin M-induced Senescence

et al. 2017

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Cytokines in the developing tumor microenvironment (TME) can drive transformation and subsequent progression toward metastasis. Elevated levels of the Interleukin-6 (IL-6) family cytokine Oncostatin M (OSM) in the breast TME correlate with aggressive, metastatic cancers, increased tumor recurrence, and poor patient prognosis. Paradoxically, OSM engages a tumor-suppressive, Signal Transducer and Activator of Transcription 3 (STAT3)-dependent senescence response in normal and non-transformed human mammary epithelial cells (HMEC). Here, we identify a novel link between OSM-activated STAT3 signaling and the Transforming Growth Factor-b (TGF-b) signaling pathway that engages senescence in HMEC. Inhibition of functional TGF-b/SMAD signaling by expressing a dominant-negative TGF-b receptor, treating with a TGF-b receptor inhibitor, or suppressing SMAD3 expression using a SMAD3-shRNA prevented OSMinduced senescence. OSM promoted a protein complex involving activated-STAT3 and SMAD3, induced the nuclear localization of SMAD3, and enhanced SMAD3-mediated transcription responsible for senescence. In contrast, expression of MYC (c-MYC) from a constitutive promoter abrogated senescence and strikingly, cooperated with OSM to promote a transformed phenotype, epithelial-mesenchymal transition (EMT), and invasiveness. Our findings suggest that a novel STAT3/SMAD3-signaling axis is required for OSM-mediated senescence that is coopted during the transformation process to confer aggressive cancer cell properties. Understanding how developing cancer cells bypass OSM/STAT3/SMAD3-mediated senescence may help identify novel targets for future "pro-senescence" therapies aiming to reengage this hidden tumor-suppressive response.

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MYC and Metastasis

Cited by 158 publications

References 39 publications

HSPC111 Governs Breast Cancer Growth by Regulating Ribosomal Biogenesis

HSPC111 Governs Breast Cancer Growth by Regulating Ribosomal Biogenesis

The Soy Isoflavone Equol May Increase Cancer Malignancy via Up-regulation of Eukaryotic Protein Synthesis Initiation Factor eIF4G

STAT3-mediated SMAD3 activation underlies Oncostatin M-induced Senescence

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