Modelling Myc inhibition as a cancer therapy

Soucek, Laura; Whitfield, Jonathan R.; Martins, Carla P.; Finch, Andrew J.; Murphy, Daniel J.; Sodir, Nicole M.; Karnezis, Anthony N.; Swigart, Lamorna Brown; Nasi, Sergio; Evan, Gérard I.

doi:10.1038/nature07260

Cited by 731 publications

(737 citation statements)

References 29 publications

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“…There has been much debate over whether c-Myc is a therapeutic target for colorectal cancer and the difficulties regarding targeting c-Myc using small molecules (Soucek et al, 2008;Wilkins and Sansom, 2008). Our study here suggests that reduction of c-Myc (as well as complete ablation) may be a rationale for chemoprevention of colorectal cancer.…”

mentioning

confidence: 72%

Myc heterozygosity attenuates the phenotypes of APC deficiency in the small intestine

Athineos

Sansom

2010

Oncogene

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mentioning

confidence: 72%

Myc heterozygosity attenuates the phenotypes of APC deficiency in the small intestine

Athineos

Sansom

2010

Oncogene

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“…In the future, identification of MYC-positive primary cutaneous angiosarcomas may prove to be of clinical significance, especially in the context of new therapeutic approaches targeting the MYC pathway. 1,13 Disclosure/conflict of interest…”

Section: Discussionmentioning

confidence: 99%

MYC amplification and overexpression in primary cutaneous angiosarcoma: a fluorescence in-situ hybridization and immunohistochemical study

et al. 2014

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MYC, a proto-oncogene located on chromosome 8q24, is involved in the control of cell proliferation and differentiation. Previous studies have documented high-level MYC gene amplification and MYC overexpression by immunohistochemistry (IHC) in post-irradiation angiosarcomas, but not in primary cutaneous angiosarcoma (AS-C) or in other radiation-associated vascular proliferations, such as atypical vascular lesions. Prompted by our recent finding of MYC amplification in a primary hepatic AS, we analyzed a large number of wellcharacterized AS-C for MYC amplification and protein overexpression. Formalin-fixed, paraffin-embedded blocks from 38 AS-C were retrieved from our archives and were examined by IHC analysis and fluorescence in-situ hybridization (FISH), using a commercially available antibody and probe. For FISH analysis, the number of copies of MYC was compared with the control gene, CEN8 (MYC/CEN8 ratio). All cases occurred on sunexposed skin; no patient was known to have a history of therapeutic irradiation. Possible associations between survival and a wide variety of clinicopathological variables were evaluated using the log-rank test. By IHC analysis, MYC overexpression was present in 9/38 (24%) AS-C (2-3 þ : 6 cases, 16%; 1 þ : 3 cases, 8%). By FISH analysis, 2/5 (40%) informative cases with 2-3 þ immunostaining showed high-level gene amplification. One additional case with 3 þ immunostaining showed higher level aneusomy of chromosome 8 (5-8 MYC and CEN8). Two out of fourteen (14%) IHC-negative cases also carried MYC amplification (one high level and one lower level). Low copy number gain of chromosome 8 (3-5 MYC and CEN8) was observed in AS-C with or without MYC expression. MYC amplification and MYC protein overexpression were not correlated with clinical outcome. We have shown, for the first time, MYC gene amplification and protein overexpression in primary (non-radiation-associated) AS of the skin. MYC protein overexpression in cases lacking gene amplification likely reflects other mechanisms of MYC activation. The study of a larger number of AS-C showing MYC amplification may be necessary to determine whether the behavior of such cases differs from their more common non-amplified counterparts.

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“…12 MYC deregulation by amplification has been noted in many solid tumors, and recent work emphasizes its role as an important anticancer target. 13 In regard to soft tissue sarcomas, MYC overexpression and increased MYC copy numbers are frequent in high-grade chondrosarcomas, 14 epithelioid sarcomas of the proximal type, 15 in higher-grade myxoid liposarcomas, 16 and have an adverse prognostic impact in leiomyosarcomas of soft tissues. 17 A recent study reported MYC high-level gene amplification in postradiation cutaneous angiosarcomas and in chronic lymphedema-associated cutaneous angiosarcomas (so-called secondary angiosarcomas), whereas so-called primary angiosarcomas of skin, soft tissues, bone, and visceral organs were negative.…”

Section: Postradiation Angiosarcomamentioning

confidence: 99%

Postradiation cutaneous angiosarcoma after treatment of breast carcinoma is characterized by MYC amplification in contrast to atypical vascular lesions after radiotherapy and control cases: clinicopathological, immunohistochemical and molecular analysis of 66 cases

et al. 2012

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Postradiation cutaneous angiosarcoma after treatment of breast carcinoma is characterized by MYC amplification in contrast to atypical vascular lesions after radiotherapy and control cases: clinicopathological, immunohistochemical and molecular analysis of 66 cases Postradiation cutaneous vascular lesions after treatment of breast carcinoma comprise a heterogeneous group of benign, atypical, and malignant lesions and are best regarded as points along a morphological spectrum. We analyzed a series of cutaneous angiosarcomas after treatment of breast cancer in comparison with control cases and cases of atypical vascular lesions with special emphasis on the expression and amplification of MYC. The 66 cases were divided into control cases (5), cases in which a slight vascular proliferation was seen after radiotherapy of breast cancer (12), cases of atypical vascular lesions after radiotherapy (16), cases of postradiation cutaneous angiosarcomas (25), and cases of angiosarcomas of skin and soft tissues unrelated to radiotherapy (8). None of the control cases (2 M, 3 F, 20-76 years), of cases showing slight vascular proliferation, dermal fibrosis and inflammation after radiotherapy of breast cancer (12 F, 48-79 years), of cases of atypical vascular lesions after radiotherapy (16 F, 29-81 years), and of cases of angiosarcomas of skin and soft tissues unrelated to radiotherapy (3 M, 5 F, 25-92 years) showed an amplification of MYC by FISH analysis. In striking contrast, in all cases of postradiation cutaneous angiosarcomas (25 F, 46-95 years), MYC amplification was found by FISH analysis in a variable number of counted nuclei. Immunohistochemically, strong positive nuclear staining for MYC and prox-1 was seen in cases of postradiation cutaneous angiosarcoma, whereas control cases and cases of atypical vascular proliferation after radiotherapy were negative for MYC, and stained only focally positive for prox-1 in a number of cases. In conclusion, the presence of MYC amplification represents an important additional diagnostic tool in the distinction of postradiation cutaneous angiosarcomas from atypical vascular lesions after radiotherapy. Immunohistochemical stainings for MYC are useful for mapping of these lesions and for careful tumor margin control.

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Modelling Myc inhibition as a cancer therapy

Cited by 731 publications

References 29 publications

Myc heterozygosity attenuates the phenotypes of APC deficiency in the small intestine

Myc heterozygosity attenuates the phenotypes of APC deficiency in the small intestine

MYC amplification and overexpression in primary cutaneous angiosarcoma: a fluorescence in-situ hybridization and immunohistochemical study

Postradiation cutaneous angiosarcoma after treatment of breast carcinoma is characterized by MYC amplification in contrast to atypical vascular lesions after radiotherapy and control cases: clinicopathological, immunohistochemical and molecular analysis of 66 cases

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