MGMT inhibition restores ERα functional sensitivity to antiestrogen therapy
Authors: Beth Isley
Susan M Constantino
Santhi D Konduri
Sreeram Maddipatla
Arati Limaye
Cheryl H Baker
George C Bobustuc
Said Baidas
Maria-Lourdes M Caparas
Kalkunte S Srivenugopal
Sheila Jeudy
Nikita Shah
Joshua S Smith
Journal: Molecular Medicine (2012)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Antiestrogen therapy resistance; O(6) methylguanine DNA methyl transferase (MGMT); tamoxifen resistance; estrogen receptor alpha (ERα); O(6)-benzylguanine (BG)
Affiliations: MD Anderson Cancer Center Orlando, Orlando, Florida 32827, United States of America. 

Abstract:  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. In tamoxifen-resistant breast cancer cells, BG alone or in combination with antiestrogen (tamoxifen [TAM]/ICI 182,780 [fulvestrant, Faslodex]) therapy enhances p53 upregulated modulator of apoptosis (PUMA) expression, cytochrome C release and poly (ADP-ribose) polymerase (PARP) cleavage, all indicative of apoptosis. In addition, BG increases the expression of p21(cip1/waf1). 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. 

Retracted: No

PubPeer comments:
 Figure 6. * In yellow and bright green: Two possible pairs of overlapping photos in the p53 row * In light purple: A possible pair of overlapping photos in the p21 row * In pink, orange, teal, and dark green: Possible overlaps with photos in two other papers by this group, i.e. Bobustuc et al., Oncotarget (2018), doi: 10.18632 oncotarget.25696, https: pubpeer.com publications 224D88DC5ED363E77E9270E4A846DA and J.S. Smith et al., Anti-cancer agents in medicinal chemistry (2010), pubmed: 21184665, https: pubpeer.com publications 4AE7CF2D86AE304AED6E6894BCEC28 ![file] Here is a composite of the figures from 2010 and 2018 with potential overlapping images. ![file] , 
 Figure 7C. Two panels appear to show an overlap. ![file] , 
 Figure 5  ICI and  BG appear to be different pictures of the same mice. Fine features match in these two pictures. ![file] ,