TY - JOUR
T1 - Cyclooxygenase-2 protein reduces tamoxifen and N-(4-hydroxyphenyl) retinamide inhibitory effects in breast cancer cells
AU - Tari, Ana M.
AU - Simeone, Ann Marie
AU - Li, Yu Jiang
AU - Gutierrez-Puente, Yolanda
AU - Lai, Syeling
AU - Symmans, William F.
N1 - Funding Information:
We thank Karen M Ramirez and The University of Texas MD Anderson Cancer Center, Department of Immunology Flow Cytometry Core Laboratory for their technical assistance. This research was supported in part by the instiutiton’s NCI Core Grant (CA 16672), the Cancer Research and Prevention Foundation (to A-M Simeone) and the Susan G Komen Breast Cancer Foundation (to AM Tari).
PY - 2005/11
Y1 - 2005/11
N2 - Approximately 30-40% of estrogen receptor α (ERα)-positive breast tumors express high levels of the cyclooxygenase-2 (COX-2) protein, and these high levels have been associated with a poorer prognosis in breast cancer patients. We speculate that high levels of COX-2 induce drug resistance in ERα-positive breast tumors, thus reducing the survival rate of patients with such tumors. Human breast cancer cell lines that express high levels of COX-2 are generally ERα negative. To determine whether COX-2 induces drug resistance, plasmids encoding the COX-2 gene were stably transfected into ERα-positive MCF-7 human breast cancer cells (MCF-7/COX-2). MCF-7/COX-2 cells were resistant to the selective estrogen receptor modulator tamoxifen but not to its analog, raloxifene. MCF-7/COX-2 cells were also resistant to the retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) but not to its analog, all-trans retinoic acid. In contrast, the sensitivities of MCF-7/COX-2 cells to doxorubicin and paclitaxel were similar to those of the parental MCF-7 cells. We then determined which COX-2 product, prostaglandin E2 (PGE 2) or prostaglandin F2α is involved in the COX-2-mediated drug resistance. PGE2, but not PGF2α, blocked the antiproliferative effects of tamoxifen and 4-HPR. Agonists that activate PGE2receptors and their downstream kinase effectors, protein kinases A and C, also blocked the growth inhibitory effects of these drugs. Increased levels of Bcl-2 and Bcl-XL proteins have been reported in mammary tumors of COX-2 transgenic mice and in human colon cancer cell lines that have high levels of COX-2. However, we did not observe any changes in Bcl-2, Bcl-XL, or Bax expression induced by COX-2 or PGE2. Here we report the novel findings that COX-2 uses PGE2 to stimulate the activities of protein kinases A and C to induce selectively tamoxifen and 4-HPR resistance in ERα-positive breast cancer cells.
AB - Approximately 30-40% of estrogen receptor α (ERα)-positive breast tumors express high levels of the cyclooxygenase-2 (COX-2) protein, and these high levels have been associated with a poorer prognosis in breast cancer patients. We speculate that high levels of COX-2 induce drug resistance in ERα-positive breast tumors, thus reducing the survival rate of patients with such tumors. Human breast cancer cell lines that express high levels of COX-2 are generally ERα negative. To determine whether COX-2 induces drug resistance, plasmids encoding the COX-2 gene were stably transfected into ERα-positive MCF-7 human breast cancer cells (MCF-7/COX-2). MCF-7/COX-2 cells were resistant to the selective estrogen receptor modulator tamoxifen but not to its analog, raloxifene. MCF-7/COX-2 cells were also resistant to the retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) but not to its analog, all-trans retinoic acid. In contrast, the sensitivities of MCF-7/COX-2 cells to doxorubicin and paclitaxel were similar to those of the parental MCF-7 cells. We then determined which COX-2 product, prostaglandin E2 (PGE 2) or prostaglandin F2α is involved in the COX-2-mediated drug resistance. PGE2, but not PGF2α, blocked the antiproliferative effects of tamoxifen and 4-HPR. Agonists that activate PGE2receptors and their downstream kinase effectors, protein kinases A and C, also blocked the growth inhibitory effects of these drugs. Increased levels of Bcl-2 and Bcl-XL proteins have been reported in mammary tumors of COX-2 transgenic mice and in human colon cancer cell lines that have high levels of COX-2. However, we did not observe any changes in Bcl-2, Bcl-XL, or Bax expression induced by COX-2 or PGE2. Here we report the novel findings that COX-2 uses PGE2 to stimulate the activities of protein kinases A and C to induce selectively tamoxifen and 4-HPR resistance in ERα-positive breast cancer cells.
KW - 4-HPR (fenretinide)
KW - Breast cancer chemoprevention
KW - COX-2
KW - PGE
KW - Tamoxifen
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U2 - 10.1038/labinvest.3700339
DO - 10.1038/labinvest.3700339
M3 - Article
C2 - 16127422
AN - SCOPUS:27144548430
SN - 0023-6837
VL - 85
SP - 1357
EP - 1367
JO - Laboratory Investigation
JF - Laboratory Investigation
IS - 11
ER -