Inverse Correlation Between the Expression of O6-Methylguanine-DNA Methyl Transferase (MGMT) and p53 in Breast Cancer

Osanai, Takayuki; Takagi, Yoko; Toriya, Yoichi; Nakagawa, Tsuyoshi; Aruga, Tomoyuki; Iida, Satoru; Uetake, Hiroyuki; Sugihara, Kenichi

doi:10.1093/jjco/hyi036

Cited by 38 publications

(37 citation statements)

References 10 publications

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“…Interobserver reproducibility of immunohistochemical scoring is sometimes problematic. However, interobserver variations were easily resolved by re-evaluation and discussion to reach consensus because MGMT immunostaining is distinct and reliable in the present study as well as previous reports [28,29]. In this study, patients with attenuated MGMT expression in their lesions had a 2.3 times higher probability of achieving a pCR than those with preserved expression.…”

Section: Discussionsupporting

confidence: 70%

“…In contrast, MGMT gene expression measured by reverse transcription-PCR was not predictive of response to neoadjuvant chemotherapy [27]. MGMT immunoreactivity has been reported to be correlated with local recurrence, distant metastasis and prognosis in breast carcinoma [28,29]. To the best of our knowledge, there is no report of relationship between MGMT immunoreactivity and response to neoadjuvant chemotherapy.…”

Section: Discussionmentioning

confidence: 96%

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Predictive value of MGMT, hMLH1, hMSH2 and BRCA1 protein expression for pathological complete response to neoadjuvant chemotherapy in basal-like breast cancer patients

Nakai

Mitomi

Yimit

et al. 2011

Cancer Chemother Pharmacol

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 96%

Predictive value of MGMT, hMLH1, hMSH2 and BRCA1 protein expression for pathological complete response to neoadjuvant chemotherapy in basal-like breast cancer patients

Nakai

Mitomi

Yimit

et al. 2011

Cancer Chemother Pharmacol

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“…IRFs and S100A11 are well known in the apoptotic signaling (38). Although the function of N-methyltransferase is still unclear, some methyltransferases are known to be involved in cancer metastases (44).…”

Section: Discussionmentioning

confidence: 99%

Possible Involvement of RUNX3 Silencing in the Peritoneal Metastases of Gastric Cancers

Sakakura¹,

Hasegawa

Miyagawa³

et al. 2005

Clinical Cancer Research

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Purpose: Our previous results suggested that a lackof RUNX3 function contributed tohumangastric carcinogenesis, but the role of RUNX3 inprogression and metastasis remains unclear.We examined RUNX3 expression in clinical samples of peritoneal metastases in gastric cancers. Changes in metastatic potential were assessed in animal experiments using stable RUNX3 transfectants of gastric cancer cells. Finally, global expression changes were analyzed using a cDNA microarray. Experimental Design and Results: Significant down-regulation of RUNX3 through methylation on the promoter region was observed in primary tumors (75%) as well as in all clinical peritoneal metastases of gastric cancers (100 %) compared with normal gastric mucosa. Stable transfection of RUNX3 inhibited cell proliferation slightly, and modest transforming growth factor-h (TGF-h)^induced antiproliferative and apoptotic effects were observed. Interestingly, it strongly inhibited peritoneal metastases of gastric cancers in animal model (P < 0.01). Furthermore, we did globally analyzed expression profiles of f21,000 genes in parent cells and stable transfectant of RUNX3 using a cDNA microarray. Microarray analysis identified f28 candidate genes under the possible downstream control of RUNX3, some of these genes were considered to be possibly involved in peritoneal metastases, which were related to signal transduction (vav3, TOLL-like receptor, MAPKK, MET, S1 00A11, and cathepsin E), apoptosis (caspase 9), immune responses (CD55 and TLR1O), and cell adhesion (sialyltransferase 1 and galectin 4). Some of the genes are involved in theTGF-h signaling pathway. Conclusion: These results indicate that silencing of RUNX3 affects expression of important genes involved in aspects of metastasis including cell adhesion, proliferation, apoptosis, and promoting the peritoneal metastasis of gastric cancer. Identification of such genes could suggest new therapeutic modalities and therapeutic targets.

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“…There is an inverse correlation between the levels of MGMT and p53 tumor suppressor protein (46), where wild-type p53 suppresses transcription of MGMT expression (47) by direct binding to the MGMT promoter (48). Unfortunately p53 is often inactivated or suppressed in cancers and restoration of p53 activity remains essential to the success of some treatments.…”

Section: Introductionmentioning

confidence: 99%

MGMT Inhibition Restores ERα Functional Sensitivity to Antiestrogen Therapy

Bobustuc

Smith

Maddipatla

et al. 2012

Mol Med

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Antiestrogen therapy resistance remains a huge stumbling block in the treatment of breast cancer. We have found significant elevation of O 6 methylguanine DNA methyl transferase (MGMT) expression in a small sample of consecutive patients who have failed tamoxifen treatment. Here, we show that tamoxifen resistance is accompanied by upregulation of MGMT. Further we show that administration of the MGMT inhibitor, O 6 -benzylguanine (BG), at nontoxic doses, leads to restoration of a favorable estrogen receptor alpha (ERα) phosphorylation phenotype (high p-ERα Ser167/low p-ERα Ser118), which has been reported to correlate with sensitivity to endocrine therapy and improved survival. We also show BG to be a dual inhibitor of MGMT and ERα. . We also show that BG, alone or in combination therapy, curtails the growth of tamoxifen-resistant breast cancer in vitro and in vivo. In tamoxifen-resistant MCF7 breast cancer xenografts, BG alone or in combination treatment causes significant delay in tumor growth. Immunohistochemistry confirms that BG increases p21 cip1/waf1 and p-ERα Ser167 expression and inhibits MGMT, ERα, p-ERα Ser118 and ki-67 expression. Collectively, our results suggest that MGMT inhibition leads to growth inhibition of tamoxifen-resistant breast cancer in vitro and in vivo and resensitizes tamoxifen-resistant breast cancer cells to antiestrogen therapy. These findings suggest that MGMT inhibition may provide a novel therapeutic strategy for overcoming antiestrogen resistance.

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Inverse Correlation Between the Expression of O6-Methylguanine-DNA Methyl Transferase (MGMT) and p53 in Breast Cancer

Abstract: p53 may be associated with the regulation of MGMT expression in breast cancers.

Cited by 38 publications

References 10 publications

Predictive value of MGMT, hMLH1, hMSH2 and BRCA1 protein expression for pathological complete response to neoadjuvant chemotherapy in basal-like breast cancer patients

Predictive value of MGMT, hMLH1, hMSH2 and BRCA1 protein expression for pathological complete response to neoadjuvant chemotherapy in basal-like breast cancer patients

Possible Involvement of RUNX3 Silencing in the Peritoneal Metastases of Gastric Cancers

MGMT Inhibition Restores ERα Functional Sensitivity to Antiestrogen Therapy

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