Annals of Surgical Oncology, Vol 2, Issue 3 238-245, Copyright © 1995 by Society of Surgical Oncology

ARTICLES

Effects of tamoxifen on growth and apoptosis of estrogen-dependent and -independent human breast cancer cells

R. R. Perry, Y. Kang and B. Greaves
Division of Surgical Oncology, Eastern Virginia Medical School, Norfolk 23507-1912, USA.

BACKGROUND: Apoptosis ("programmed cell death") is an active process characterized by prominent nuclear changes and DNA cleavage, which distinguishes it from cellular necrosis. In this study we investigated whether tamoxifen (TAM) treatment of estrogen receptor ER(+) MCF-7 and ER(-) MDA-231 human breast cancer cells resulted in cytotoxicity and cellular changes typical of apoptosis. METHODS: Cytotoxicity was measured using a tetrazolium assay. Cellular morphologic changes were observed using transmission electron microscopy. DNA cleavage was assessed using 1.6% agarose gel electrophoresis and was also quantitated biochemically. RESULTS: Exposure of cells to TAM for 24 h resulted in dose-dependent cytotoxicity, and MCF-7 cells were somewhat more sensitive to TAM. TAM induced chromatin condensation around the nuclear periphery in both cell lines, changes typical of apoptosis. TAM-induced cytotoxicity correlated with dose-dependent DNA cleavage, which showed the characteristic "internucleosomal ladder." DNA cleavage occurred at a slightly lower TAM dose and occurred somewhat sooner in MCF-7 cells. TAM-induced DNA cleavage in MCF-7 cells was inhibited by the protein synthesis inhibitor cycloheximide, the RNA synthesis inhibitor actinomycin D, and by 17 beta-estradiol. However, in MDA-231 cells, DNA cleavage was inhibited by cycloheximide, partially but not significantly inhibited by actinomycin D, and not inhibited by 17 beta-estradiol. CONCLUSIONS: TAM induces typical apoptosis in ER(+) or ER(-) human breast cancer cells. TAM induction of apoptosis in MCF-7 cells involves the estrogen receptor, and requires the synthesis of new protein and mRNA. TAM induction of apoptosis in MDA-231 cells depends primarily on protein synthesis. TAM-induced cytotoxicity and DNA damage appear to be explained in part by the induction of apoptosis.

This article has been cited by other articles:

				A. Zheng, A. Kallio, and P. Harkonen Tamoxifen-Induced Rapid Death of MCF-7 Breast Cancer Cells Is Mediated via Extracellularly Signal-Regulated Kinase Signaling and Can Be Abrogated by Estrogen Endocrinology, June 1, 2007; 148(6): 2764 - 2777. [Abstract] [Full Text] [PDF]

				E. H. Ahn, C.-C. Chang, and J. J. Schroeder Evaluation of sphinganine and sphingosine as human breast cancer chemotherapeutic and chemopreventive agents. Experimental Biology and Medicine, November 1, 2006; 231(10): 1664 - 1672. [Abstract] [Full Text] [PDF]

				B. Ratliff, E. C. Dietze, G. R. Bean, C. Moore, S. Wanko, and V. L. Seewaldt Re: Active Tamoxifen Metabolite Plasma Concentrations After Coadministration of Tamoxifen and the Selective Serotonin Reuptake Inhibitor Paroxetine J Natl Cancer Inst, June 2, 2004; 96(11): 883 - 883. [Full Text] [PDF]

				W. Somboonporn and S. R. Davis Testosterone Effects on the Breast: Implications for Testosterone Therapy for Women Endocr. Rev., June 1, 2004; 25(3): 374 - 388. [Abstract] [Full Text] [PDF]

				S. Mabuchi, M. Ohmichi, A. Kimura, Y. Ikebuchi, K. Hisamoto, E. Arimoto-Ishida, Y. Nishio, K. Takahashi, K. Tasaka, and Y. Murata Tamoxifen Inhibits Cell Proliferation via Mitogen-Activated Protein Kinase Cascades in Human Ovarian Cancer Cell Lines in a Manner Not Dependent on the Expression of Estrogen Receptor or the Sensitivity to Cisplatin Endocrinology, March 1, 2004; 145(3): 1302 - 1313. [Abstract] [Full Text] [PDF]

				I. Girault, F. Lerebours, S. Amarir, S. Tozlu, M. Tubiana-Hulin, R. Lidereau, and I. Bieche Expression Analysis of Estrogen Receptor {alpha} Coregulators in Breast Carcinoma: Evidence That NCOR1 Expression Is Predictive of the Response to Tamoxifen Clin. Cancer Res., April 1, 2003; 9(4): 1259 - 1266. [Abstract] [Full Text] [PDF]

				G. Ferrandina, F. O. Ranelletti, L. M. Larocca, N. Maggiano, E. Fruscella, F. Legge, G. Santeusanio, A. Bombonati, S. Mancuso, and G. Scambia Tamoxifen Modulates the Expression of Ki67, Apoptosis, and Microvessel Density in Cervical Cancer Clin. Cancer Res., September 1, 2001; 7(9): 2656 - 2661. [Abstract] [Full Text] [PDF]

				A. Chiarenza, P. Lazarovici, L. Lempereur, G. Cantarella, A. Bianchi, and R. Bernardini Tamoxifen Inhibits Nerve Growth Factor-induced Proliferation of the Human Breast Cancerous Cell Line MCF-7 Cancer Res., April 1, 2001; 61(7): 3002 - 3008. [Abstract] [Full Text]

				V. L. Seewaldt, K. Mrózek, E. C. Dietze, M. Parker, and L. E. Caldwell Human Papillomavirus Type 16 E6 Inactivation of p53 in Normal Human Mammary Epithelial Cells Promotes Tamoxifen-mediated Apoptosis Cancer Res., January 1, 2001; 61(2): 616 - 624. [Abstract] [Full Text]

				S. Mandlekar, R. Yu, T.-H. Tan, and A.-N. T. Kong Activation of Caspase-3 and c-Jun NH2-terminal Kinase-1 Signaling Pathways in Tamoxifen-induced Apoptosis of Human Breast Cancer Cells Cancer Res., November 1, 2000; 60(21): 5995 - 6000. [Abstract] [Full Text]

				A. Gandhi, P. A. Holland, W. F. Knox, C. S. Potten, and N. J. Bundred Effects of a Pure Antiestrogen on Apoptosis and Proliferation within Human Breast Ductal Carcinoma in Situ Cancer Res., August 1, 2000; 60(15): 4284 - 4288. [Abstract] [Full Text]

				C. C. Zhang and D. J. Shapiro Activation of the p38 Mitogen-activated Protein Kinase Pathway by Estrogen or by 4-Hydroxytamoxifen Is Coupled to Estrogen Receptor-induced Apoptosis J. Biol. Chem., January 7, 2000; 275(1): 479 - 486. [Abstract] [Full Text] [PDF]

				G.-J. Zhang, I. Kimijima, M. Onda, M. Kanno, H. Sato, T. Watanabe, A. Tsuchiya, R. Abe, and S. Takenoshita Tamoxifen-induced Apoptosis in Breast Cancer Cells Relates to Down-Regulation of bcl-2, but not bax and bcl-XL, without Alteration of p53 Protein Levels Clin. Cancer Res., October 1, 1999; 5(10): 2971 - 2977. [Abstract] [Full Text] [PDF]

				G. Pan, S. M. Vickers, A. Pickens, J. O. Phillips, W. Ying, J. A. Thompson, G. P. Siegal, and J. M. McDonald Apoptosis and Tumorigenesis in Human Cholangiocarcinoma Cells : Involvement of Fas/APO-1 (CD95) and Calmodulin Am. J. Pathol., July 1, 1999; 155(1): 193 - 203. [Abstract] [Full Text] [PDF]

				J. I. Macgregor and V. C. Jordan Basic Guide to the Mechanisms of Antiestrogen Action Pharmacol. Rev., June 1, 1998; 50(2): 151 - 196. [Abstract] [Full Text] [PDF]

				L. M. Scavo, R. Ertsey, C. J. Chapin, L. Allen, and J. A. Kitterman Apoptosis in the Development of Rat and Human Fetal Lungs Am. J. Respir. Cell Mol. Biol., January 1, 1998; 18(1): 21 - 31. [Abstract] [Full Text]

				H. M. Ellerby, S. J. Martin, L. M. Ellerby, S. S. Naiem, S. Rabizadeh, G. S. Salvesen, C. A. Casiano, N. R. Cashman, D. R. Green, and D. E. Bredesen Establishment of a Cell-Free System of Neuronal Apoptosis: Comparison of Premitochondrial, Mitochondrial, and Postmitochondrial Phases J. Neurosci., August 15, 1997; 17(16): 6165 - 6178. [Abstract] [Full Text] [PDF]

				K. D. Burroughs, K. Kiguchi, S. R. Howe, R. Fuchs-Young, D. Trono, J. C. Barrett, and C. Walker Regulation of Apoptosis in Uterine Leiomyomata Endocrinology, July 1, 1997; 138(7): 3056 - 3064. [Abstract] [Full Text] [PDF]

				E. C. Dietze, L. E. Caldwell, S. L. Grupin, M. Mancini, and V. L. Seewaldt Tamoxifen but Not 4-Hydroxytamoxifen Initiates Apoptosis in p53(-) Normal Human Mammary Epithelial Cells by Inducing Mitochondrial Depolarization J. Biol. Chem., February 9, 2001; 276(7): 5384 - 5394. [Abstract] [Full Text] [PDF]