This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by John, S. Articles by Thomas, T.J. Search for Related Content PubMed PubMed Citation Articles by John, S. Articles by Thomas, T.J.

Regulation of Estrogenic Effects by Beclin 1 in Breast Cancer Cells

¹ Departments of Medicine, ² Environmental and Occupational Medicine, and ³ Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey; ⁴ Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and ⁵ Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York

Requests for reprints: T.J. Thomas, Clinical Academic Building, Room 7090, 125 Paterson Street, New Brunswick, NJ 08903. Phone: 732-235-8460; Fax: 732-235-8473; E-mail: thomastj{at}umdnj.edu.

Key Words: Beclin 1 • antiestrogen resistance • breast cancer

Beclin 1 is an essential mediator of autophagy and a regulator of cell growth and cell death. We examined the effect of Beclin 1 overexpression on the action of estradiol (E₂) and two antiestrogens, raloxifene and 4-hydroxytamoxifen, in estrogen receptor (ER)-positive MCF-7 breast cancer cells. [³H]-thymidine incorporation studies showed that Beclin 1–overexpressing cells (MCF-7.beclin) had a lower proliferative response to E₂ compared with cells transfected with vector control (MCF-7.control). There was only a 35% increase in [³H]-thymidine incorporation, after 24 hours of E₂ treatment of MCF-7.beclin cells compared with untreated cells, whereas this increase was 2-fold for MCF-7.control cells. E₂-induced changes in the expression of early-response genes were examined by real-time quantitiative PCR. There were significant differences in the pattern of expression of E₂-induced genes c-myc, c-fos, Erg-1, and Nur77 between MCF-7.beclin and MCF-7.control cells two hours after treatment. Although E₂-induced growth of MCF-7.control cells was completely inhibited by 500 nmol/L raloxifene or 500 nmol/L 4-hydroxytamoxifen, these concentrations of antiestrogens had no significant effect on the growth of MCF-7.beclin cells. Confocal microscopic and coimmunoprecipitation studies showed evidence for colocalization and association of Beclin 1 and ER. In addition, E₂ caused a decrease in Akt phosphorylation in MCF-7.beclin cells, compared with a 3-fold increase in MCF-7 cells, five minutes after treatment. These results indicate that Beclin 1 can down-regulate estrogenic signaling and growth response, and contribute to the development of antiestrogen resistance. This observation might be useful to define and overcome antiestrogen resistance of breast cancer. [Cancer Res 2008;68(19):7855–63]