PURPOSE: In breast cancer, the presence of estrogen receptor alpha (ER) denotes a better prognosis and response to antiestrogen therapy. Lack of ERalpha 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 ERalpha expression in a reversible manner. In this study, we determine if inhibition of MAPK in established ERalpha(-) breast cancer cell lines and tumors results in reexpression of ERalpha, and further, if reexpression of ERalpha in these ERalpha(-) tumors and cell lines could restore antiestrogen responses. EXPERIMENTAL DESIGN: Established ERalpha(-) breast cancer cell lines, ERalpha(-) breast tumors, and tumor cell cultures obtained from ERalpha(-) 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 ERalpha was used to assess the reexpression of ERalpha 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 ERalpha(-) breast cancer cell lines results in reexpression of ERalpha; upstream inhibition via targeting epidermal growth factor receptor or c-erbB-2 is equally effective. Importantly, this reexpressed ERalpha can now mediate an antiestrogen response in a subset of these ERalpha(-) breast cancer cell lines. Treatment of ERalpha(-) tumor specimens with MAPK inhibitors results in restoration of ERalpha mRNA, and similarly in epithelial cultures from ERalpha(-) tumors, MAPK inhibition restores both ERalpha protein and antiestrogen response. CONCLUSIONS: These data show both the possibility of restoring ERalpha expression and antiestrogen responses in ERalpha(-) breast cancer and suggest that there exist ERalpha(-) breast cancer patients who would benefit from a combined MAPK inhibition/hormonal therapy.
PURPOSE: In breast cancer, the presence of estrogen receptor alpha (ER) denotes a better prognosis and response to antiestrogen therapy. Lack of ERalpha 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 ERalpha expression in a reversible manner. In this study, we determine if inhibition of MAPK in established ERalpha(-) breast cancer cell lines and tumors results in reexpression of ERalpha, and further, if reexpression of ERalpha in these ERalpha(-) tumors and cell lines could restore antiestrogen responses. EXPERIMENTAL DESIGN: Established ERalpha(-) breast cancer cell lines, ERalpha(-) breast tumors, and tumor cell cultures obtained from ERalpha(-) 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 ERalpha was used to assess the reexpression of ERalpha 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 ERalpha(-) breast cancer cell lines results in reexpression of ERalpha; upstream inhibition via targeting epidermal growth factor receptor or c-erbB-2 is equally effective. Importantly, this reexpressed ERalpha can now mediate an antiestrogen response in a subset of these ERalpha(-) breast cancer cell lines. Treatment of ERalpha(-) tumor specimens with MAPK inhibitors results in restoration of ERalpha mRNA, and similarly in epithelial cultures from ERalpha(-) tumors, MAPK inhibition restores both ERalpha protein and antiestrogen response. CONCLUSIONS: These data show both the possibility of restoring ERalpha expression and antiestrogen responses in ERalpha(-) breast cancer and suggest that there exist ERalpha(-) breast cancerpatients who would benefit from a combined MAPK inhibition/hormonal therapy.
Authors: D Zhao; C Pan; J Sun; C Gilbert; K Drews-Elger; D J Azzam; M Picon-Ruiz; M Kim; W Ullmer; D El-Ashry; C J Creighton; J M Slingerland Journal: Oncogene Date: 2014-08-25 Impact factor: 9.867
Authors: Carlos L Arteaga; Anne O'Neill; Stacy L Moulder; Michael Pins; Joseph A Sparano; George W Sledge; Nancy E Davidson Journal: Clin Cancer Res Date: 2008-10-01 Impact factor: 12.531