1. ¹Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2. ²Department of Surgical Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
3. ³Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Correspondence: Dr AM Tari, PhD, Section of Immunobiology and Drug Carriers, Department of Experimental Therapeutics, Unit 422, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA. E-mail: atari@mdanderson.org

Received 27 January 2005; Revised 6 July 2005; Accepted 7 July 2005; Published online 22 August 2005.

Abstract

Approximately 30–40% of estrogen receptor (ER)-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 ER-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 ER negative. To determine whether COX-2 induces drug resistance, plasmids encoding the COX-2 gene were stably transfected into ER-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 F₂ is involved in the COX-2-mediated drug resistance. PGE₂, but not PGF₂, 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-X_L 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-X_L, 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 ER-positive breast cancer cells.