The role of estrogen receptor alpha in mediating chemoresistance in breast cancer cells

Jiang Zhinong, Guo Junlan, Shen Jianguo, Jin Mei, Xie Shuduo, Wang, Wang Linbo

Description

Previous studies suggested that estrogen receptor alpha (ERα) plays an important role in the chemoresistance of breast cancers. However, large random trials failed to demonstrate any benefit of the concurrent estrogen antagonist tamoxifen on the chemotherapy efficacy. Thus, in the present study, the importance of the role of ERα in the chemoresistance of breast cancer cells was investigated. Methods The ERα-transfected Bcap37 cells and natural ERα-positive T47D breast cancer cells were treated using chemotherapeutic agents with or without 17-beta estradiol (E2) pretreatment. Their viabilities were assessed using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assays. The dead cell rates were determined using propidium iodide dye exclusion tests, and the expression levels of Bcl-2 and Bax were detected through Western blot analysis. The effects of E2 on the growth of breast cancer cells were also determined via cell growth curve and cell cycle analysis. Results ERα activation by E2 increased the sensitivity of natural ERα-positive T47D breast cancer cells to chemotherapeutic agents. However, the increase in ERα expression in ERα-negative Bcap37 breast cancer cells also significantly increased their resistance. These phenomena cannot be explained by asserting that ERα mediated the chemoresistance of breast cancer cells by regulating the expression of Bcl-2 and Bax. Our findings show that ERα activation upregulated the expression of Bcl-2 in natural ERα-positive T47D breast cancer cells, whereas ERα activation by E2 downregulated and upregulated the Bcl-2 and Bax expression levels, respectively, in ERα-transfected Bcap37 cells. This phenomenon was due to the influence of ERα on the growth of breast cancer cells. Specifically, ERα activation enhanced the growth of natural ERα-positive breast cancer cells and thus increased their sensitivity to chemotherapeutic agents. However, ERα activation also inhibited the growth of ERα-transfected Bcap37 cells and increased the resistance of cancer cells to chemotherapeutic agents. Chemoresistance of ERα-transfected Bcap37 cells was only due to the specific growth inhibition by E2, which is not applicable to common ERα-positive breast cancer cells. Conclusions Although ERα was associated with chemoresistance of breast cancers, ERα itself did not mediate this resistance process.

Sujets

• Estrogen receptor alpha
• Breast cancer
• Bcl-2
• Cell growth

Informations

• Publié par: biomed
• Publié le: 01 janvier 2012
• Nombre de lectures: 4
• Langue: English
• Poids de l'ouvrage: 1 Mo

Extrait

Jianget al. Journal of Experimental & Clinical Cancer Research2012,31:42 http://www.jeccr.com/content/31/1/42

R E S E A R C HOpen Access The role of estrogen receptor alpha in mediating chemoresistance in breast cancer cells 1 22 12 2* Zhinong Jiang , Junlan Guo , Jianguo Shen , Mei Jin , Shuduo Xieand Linbo Wang

Abstract Introduction:Previous studies suggested that estrogen receptor alpha (ERα) plays an important role in the chemoresistance of breast cancers. However, large random trials failed to demonstrate any benefit of the concurrent estrogen antagonist tamoxifen on the chemotherapy efficacy. Thus, in the present study, the importance of the role of ERαin the chemoresistance of breast cancer cells was investigated. Methods:The ERαtransfected Bcap37 cells and natural ERαpositive T47D breast cancer cells were treated using chemotherapeutic agents with or without 17beta estradiol (E2) pretreatment. Their viabilities were assessed using 3[4,5dimethylthiazol2yl]2,5diphenyltetrazolium bromide assays. The dead cell rates were determined using propidium iodide dye exclusion tests, and the expression levels of Bcl2 and Bax were detected through Western blot analysis. The effects of E2 on the growth of breast cancer cells were also determined via cell growth curve and cell cycle analysis. Results:ERαactivation by E2 increased the sensitivity of natural ERαpositive T47D breast cancer cells to chemotherapeutic agents. However, the increase in ERαexpression in ERαnegative Bcap37 breast cancer cells also significantly increased their resistance. These phenomena cannot be explained by asserting that ERαmediated the chemoresistance of breast cancer cells by regulating the expression of Bcl2 and Bax. Our findings show that ERα activation upregulated the expression of Bcl2 in natural ERαpositive T47D breast cancer cells, whereas ERαactivation by E2 downregulated and upregulated the Bcl2 and Bax expression levels, respectively, in ERαtransfected Bcap37 cells. This phenomenon was due to the influence of ERαon the growth of breast cancer cells. Specifically, ERαactivation enhanced the growth of natural ERαpositive breast cancer cells and thus increased their sensitivity to chemotherapeutic agents. However, ERαactivation also inhibited the growth of ERαtransfected Bcap37 cells and increased the resistance of cancer cells to chemotherapeutic agents. Chemoresistance of ERαtransfected Bcap37 cells was only due to the specific growth inhibition by E2, which is not applicable to common ERαpositive breast cancer cells. Conclusions:Although ERαwas associated with chemoresistance of breast cancers, ERαitself did not mediate this resistance process. Keywords:Estrogen receptor alpha, Chemoresistance, Breast cancer, Bcl2, Cell growth

Background Estrogen Receptors alpha (ERα) are expressed in approxi mately 65% of breast cancer cases. Binding of estrogen (such as estradiol) to ERαinduces tumor growth in most ERαpositive breast cancer cell lines [1]. Active Estrogen Receptors alpha can also inhibit apoptosis of breast cancer cells by upregulating Bcl2 expression [2]. Fulvestrant is a novel ERαantagonist with no agonist effects. It binds ERα, prevents dimerisation, and leads to the rapid degradation

* Correspondence: [e-mail] 2 Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University College of Medicine, Hangzhou, China Full list of author information is available at the end of the article

of the fulvestrant–ERαcomplex, downregulating cellular ERαlevels [3]. Our and other studies have suggested that ERαpositive breast cancer is more resistant to chemotherapy than ERαnegative cancer [49]. In vitro studies have also shown that ERαplays an important role in determining the sensitivity of breast cancer cells to chemotherapeutic agents [2,1014]. Considering the observed consistency between previous clinical and in vitro findings, it seems reasonable that ERαmediates the chemoresistane of breast cancer cells. Does ERαreally mediate the chemoresistance of breast cancer cells? We think this problem needs further investigation, because other clinical studies have

© 2012 Zhinong et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.