Acquired resistance to selective estrogen receptor modulators (SERMs) in clinical practice (tamoxifen & raloxifene) by selection pressure in breast cancer cell populations |
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| Affiliation: | 1. Laboratory of Molecular and Tumor Immunology, Robert W. Franz Cancer Center, Earle A. Chiles Research Institute, Providence Cancer Institute, Providence Portland Medical Center, Portland, OR, USA;2. Oregon Health & Science University, Portland, OR, USA;3. UbiVac, Portland, OR, USA;4. Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06877-0368, USA;1. Department of Chemistry, Manav Rachna International University, Faridabad, India;2. Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, India;3. Department of Microbiology, Guru Nanak Dev University, Amritsar 143005, India;1. Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center and Cancer Genomics Netherlands, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands;2. Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark;3. Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands;4. Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands;5. Department of Oncology, Odense University Hospital, Odense, Denmark;1. BrEAST Data Centre, Department of Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium;2. Division of Pathology, European Institute of Oncology, Milan, Italy;3. Fertility and Procreation Unit, Department of Gynecology Oncology, European Institute of Oncology, Milan, Italy;4. University of Milan, School of Medicine, Milan, Italy;5. Division of Clinical Medicine and Research, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia |
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| Abstract: | Tamoxifen, a pioneering selective estrogen receptor modulator (SERM), has long been a therapeutic choice for all stages of estrogen receptor (ER)-positive breast cancer. The clinical application of long-term adjuvant antihormone therapy for the breast cancer has significantly improved breast cancer survival. However, acquired resistance to SERM remains a significant challenge in breast cancer treatment. The evolution of acquired resistance to SERMs treatment was primarily discovered using MCF-7 tumors transplanted in athymic mice to mimic years of adjuvant treatment in patients. Acquired resistance to tamoxifen is unique because the growth of resistant tumors is dependent on SERMs. It appears that acquired resistance to SERM is initially able to utilize either E2 or a SERM as the growth stimulus in the SERM-resistant breast tumors. Mechanistic studies reveal that SERMs continuously suppress nuclear ER-target genes even during resistance, whereas they function as agonists to activate multiple membrane-associated molecules to promote cell growth. Laboratory observations in vivo further show that three phases of acquired SERM-resistance exists, depending on the length of SERMs exposure. Tumors with Phase I resistance are stimulated by both SERMs and estrogen. Tumors with Phase II resistance are stimulated by SERMs, but are inhibited by estrogen due to apoptosis. The laboratory models suggest a new treatment strategy, in which limited-duration, low-dose estrogen can be used to purge Phase II-resistant breast cancer cells. This discovery provides an invaluable insight into the evolution of drug resistance to SERMs, and this knowledge is now being used to justify clinical trials of estrogen therapy following long-term antihormone therapy. All of these results suggest that cell populations that have acquired resistance are in constant evolution depending upon selection pressure. The limited availability of growth stimuli in any new environment enhances population plasticity in the trial and error search for survival. |
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| Keywords: | Selective estrogen receptor modulator (SERM) Resistance Estrogen Estrogen-induced apoptosis |
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