Title

MGMT Inhibition Restores ER alpha Functional Sensitivity to Antiestrogen Therapy

Authors

Authors

G. C. Bobustuc; J. S. Smith; S. Maddipatla; S. Jeudy; A. Limaye; B. Isley; M. L. M. Caparas; S. M. Constantino; N. Shah; C. H. Baker; K. S. Srivenugopal; S. Baidas;S. D. Konduri

Comments

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Abbreviated Journal Title

Mol. Med.

Keywords

ESTROGEN-RECEPTOR-ALPHA; BREAST-CANCER-CELLS; O-6-METHYLGUANINE-DNA; METHYLTRANSFERASE ACTIVITY; ONCOLOGY TECHNOLOGY-ASSESSMENT; POSTMENOPAUSAL WOMEN; RANDOMIZED-TRIAL; TAMOXIFEN RESISTANCE; AROMATASE; INHIBITORS; ENDOCRINE-THERAPY; TUMOR-CELLS; Biochemistry & Molecular Biology; Cell Biology; Medicine, Research &; Experimental

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 (ER alpha) phosphorylation phenotype (high p-ER alpha Ser167/low p-ER alpha 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 ER alpha. 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-ER alpha Ser167 expression and inhibits MGMT, ER alpha, p-ER alpha 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. Online address: http://www.molmed.org doi: 10.2119/molmed.2012.00010

Journal Title

Molecular Medicine

Volume

18

Issue/Number

6

Publication Date

1-1-2012

Document Type

Article

Language

English

First Page

913

Last Page

929

WOS Identifier

WOS:000309154300002

ISSN

1076-1551

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