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Reversal of the Estrogen Receptor–Negative Phenotype in Breast Cancer and Restoration of Antiestrogen Response

Authors' Affiliations: ¹ Department of Internal Medicine, Division of Hematology/Oncology, and ² Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan; and ³ Department of Internal Medicine, Detroit Medical Center/Wayne State University, Detroit, Michigan

Requests for reprints: Dorraya El-Ashry, University of Michigan Health System, 1150 West Medical Center Drive, MSRB III, Room 5220B, Ann Arbor, MI 48109-0640. Phone: 734-764-5585; Fax: 734-734-0101; E-mail: elashryd{at}umich.edu.

Purpose: In breast cancer, the presence of estrogen receptor (ER) denotes a better prognosis and response to antiestrogen therapy. Lack of ER correlates with overexpression of epidermal growth factor receptor or c-erbB-2. We have shown that hyperactivation of mitogen-activated protein kinase (MAPK) directly represses ER expression in a reversible manner. In this study, we determine if inhibition of MAPK in established ER^– breast cancer cell lines and tumors results in reexpression of ER, and further, if reexpression of ER in these ER^– tumors and cell lines could restore antiestrogen responses.

Experimental Design: Established ER^– breast cancer cell lines, ER^– breast tumors, and tumor cell cultures obtained from ER^– tumors were used in this study. Inhibition of hyperactive MAPK was accomplished via the MAPK/ERK kinase 1/2 inhibitor U0126 or via upstream inhibition with Iressa or Herceptin. Western blotting or reverse transcription-PCR for ER was used to assess the reexpression of ER in cells treated with U0126. Growth assays with WST-1 were done to assess restoration of antiestrogen sensitivity in these cells.

Results: Inhibition of MAPK activity in ER^– breast cancer cell lines results in reexpression of ER; upstream inhibition via targeting epidermal growth factor receptor or c-erbB-2 is equally effective. Importantly, this reexpressed ER can now mediate an antiestrogen response in a subset of these ER^– breast cancer cell lines. Treatment of ER^– tumor specimens with MAPK inhibitors results in restoration of ER mRNA, and similarly in epithelial cultures from ER^– tumors, MAPK inhibition restores both ER protein and antiestrogen response.

Conclusions: These data show both the possibility of restoring ER expression and antiestrogen responses in ER^– breast cancer and suggest that there exist ER^– breast cancer patients who would benefit from a combined MAPK inhibition/hormonal therapy.

Commentary

The Dynamics of Estrogen Receptor Status in Breast Cancer: Re-shaping the Paradigm

Sara Lopez-Tarruella and Rachel Schiff
Clin. Cancer Res. 2007 13: 6921-6925. [Full Text] [PDF]

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