Loss of MTBP expression is associated with reduced survival in a biomarker‐defined subset of patients with squamous cell carcinoma of the head and neck

Vlatković, Nikolina; Elfert, Asem; Devling, Timothy; Ray-Sinha, Arpita; Gore, D M; Rubbi, Carlos P.; Dodson, Andy; Jones, A. S.; Helliwell, Tim; Jones, Terence M.; Boyd, Mark T.

doi:10.1002/cncr.25864

Cited by 22 publications

(32 citation statements)

References 74 publications

(51 reference statements)

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“…MTBP expression levels are also negatively correlated with migratory potential of HCC cells regardless of their p53 status. These results showing the role of MTBP in metastasis suppression are consistent with the previous following two find-ings: (1) Vlatkovic et al [12] show that reduced MTBP expression is correlated with poor prognosis in patients with head and neck carcinoma. (2) We demonstrate that MTBP suppresses osteosarcoma metastasis using an orthotopic mouse model [8].…”

Section: Discussionsupporting

confidence: 92%

“…Clinically, reduced MTBP expression in head and neck carcinoma was associated with reduced patient survival, and MTBP expression levels served as an independent prognostic factor in tumors having p53 mutation [12]. On the other hand, MTBP was found to be overexpressed in B-cell lymphoma and triple negative breast cancer where MTBP contributed to tumor progression by cooperating with Myc [13–15].…”

Section: Introductionmentioning

confidence: 99%

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MTBP inhibits migration and metastasis of hepatocellular carcinoma

Ranjan

Fan

et al. 2015

Clin Exp Metastasis

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Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide with increasing incidence. Despite curative surgical resection and advanced chemotherapy, its survival rate remains low. The presence of microvascular invasion and occult metastasis is one of the major causes for this poor outcome. MDM2 Binding Protein (MTBP) has been implicated in the suppression of cell migration and cancer metastasis. However, clinical significance of MTBP, particularly in human cancer, is poorly understood. Specifically, clinical relevance of MTBP in human HCC has never been investigated. Here we demonstrated that expression of MTBP was significantly reduced in human HCC tissues compared to adjacent non-tumor tissues. MTBP expression was negatively correlated with capsular/vascular invasion and lymph node metastasis. Overexpression of MTBP resulted in the suppression of the migratory and metastatic potential of HCC cells, while its downregulation increased the migration. Consistent with the previous report, MTBP endogenously bound to alpha-actinin 4 (ACTN4) and suppressed ACTN4-mediated cell migration in multiple HCC cell lines. However, MTBP also inhibited migratory potential of PLC/PRF/5 HCC cells whose migration was not altered by manipulation of ACTN4 expression. These results suggest that mechanisms behind MTBP-mediated migration suppression may not be limited to the pathway involving ACTN4 in certain cellular contexts. Additionally, as a potential mechanism for reduced MTBP expression in tumors, we found that MTBP expression was increased following the treatment with histone deacetylase inhibitors (HDIs). Our study, for the first time, provides clinical relevance of MTBP in the suppression of HCC metastasis.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

MTBP inhibits migration and metastasis of hepatocellular carcinoma

Ranjan

Fan

et al. 2015

Clin Exp Metastasis

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“…Although lower levels of MTBP have been associated with increased metastasis of tumor cells (14, 35), cancer cells were shown to downregulate proliferation and Myc in favor of movement (36). One report does show decreased MTBP expression in a subset of head and neck cancer correlated with reduced survival (37). However, the pro-proliferative function of Mtbp is supported by data that Mtbp induces proliferation in cells from multiple species.…”

Section: Discussionmentioning

confidence: 99%

Oncogenic Protein MTBP Interacts with MYC to Promote Tumorigenesis

et al. 2014

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Despite its involvement in most human cancers, MYC continues to pose a challenge as a readily tractable therapeutic target. Here we identify the MYC transcriptional cofactors TIP48 and TIP49 and MYC as novel binding partners of MTBP, a functionally undefined protein that we show is oncogenic and overexpressed in many human cancers. MTBP associated with MYC at promoters and increased MYC-mediated transcription, proliferation, neoplastic transformation and tumor development. In breast cancer specimens, we determined overexpression of both MYC and MTBP was associated with a reduction in 10-year patient survival compared to MYC overexpression alone. MTBP was also frequently co-amplified with MYC in many human cancers. Mechanistic investigations implicated associations with TIP48/TIP49 as well as MYC in MTBP function in cellular transformation and the growth of human breast cancer cells. Taken together, our findings show MTBP functions with MYC to promote malignancy, identifying this protein as a novel general therapeutic target in human cancer.

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“…It is possible that both are correct if, as has been shown for MYC (27), MTBP is temporarily downregulated when cancer cells move and is then upregulated after cancer cells seed metastatic sites and begin to proliferate again. However, there is also one report showing that decreased MTBP expression in a narrow subset of head and neck cancer correlated with reduced survival (28). Thus, although MTBP could have a tissue-specific or cancer cell mutation-specific function, much of the data suggest that in multiple hematopoietic and non-hematopoietic human cancers, including breast cancer, MTBP overexpression is selected for and contributes to cancer development and progression.…”

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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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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Loss of MTBP expression is associated with reduced survival in a biomarker‐defined subset of patients with squamous cell carcinoma of the head and neck

Cited by 22 publications

References 74 publications

MTBP inhibits migration and metastasis of hepatocellular carcinoma

MTBP inhibits migration and metastasis of hepatocellular carcinoma

Oncogenic Protein MTBP Interacts with MYC to Promote Tumorigenesis

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

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