title: Cyclooxygenase-2 protein reduces tamoxifen and N-(4-hydroxyphenyl)retinamide inhibitory effects in breast cancer cells.
abstract: Approximately 30-40% of estrogen receptor alpha (ERalpha)-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 ERalpha-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 ERalpha negative. To determine whether COX-2 induces drug resistance, plasmids encoding the COX-2 gene were stably transfected into ERalpha-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 (PGE2) or prostaglandin F2alpha is involved in the COX-2-mediated drug resistance. PGE2, but not PGF2alpha, blocked the antiproliferative effects of tamoxifen and 4-HPR. Agonists that activate PGE2 receptors 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 ERalpha-positive breast cancer cells.
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. atari@mdanderson.org
authors.forename: Ana M
authors.initials: AM
authors.lastname: Tari
authors.forename: Ann-Marie
authors.initials: AM
authors.lastname: Simeone
authors.forename: Yu-Jiang
authors.initials: YJ
authors.lastname: Li
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Gutierrez-Puente
authors.forename: Syeling
authors.initials: S
authors.lastname: Lai
authors.forename: William F
authors.initials: WF
authors.lastname: Symmans
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism*; D001943:Breast Neoplasms / Q000473:pathology; D045744:Cell Line, Tumor; D002999:Clone Cells; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D005260:Female; D017313:Fenretinide / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D008565:Membrane Proteins / Q000378:metabolism*; D020845:Selective Estrogen Receptor Modulators / Q000378:metabolism*; D013629:Tamoxifen / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D008565:Membrane Proteins; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D017313:Fenretinide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human