This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pacilio, C. Articles by Weisz, A. Search for Related Content PubMed PubMed Citation Articles by Pacilio, C. Articles by Weisz, A.

Constitutive Overexpression of Cyclin D1 Does Not Prevent Inhibition of Hormone-responsive Human Breast Cancer Cell Growth by Antiestrogens¹

Istituto di Patologia Generale e Oncologia, Facoltà di Medicina e Chirurgia, Seconda Università di Napoli, 1-80138 Naples, Italy [C. P., D. G., R. A., L. A., V. B. P., M. C., L. C., F. B., A. W.]; Centro di Endocrinologia e Oncologia Sperimentale del Consiglio Nazionale delle Ricerche and Dipartimento di Biologia e Patologia Cellulare e Molecolare ‘L. Califano’, Università ‘Federico II’, Naples, Italy [S. S.]; and Department of Tumor Biology, the Netherlands Cancer Institute, Amsterdam, the Netherlands [F. L., R. J. A. M. M.]

Cyclin D1 is a target for positive regulation by estrogens in growth-responsive cells, in which it mediates their mitogenic effects. Amplification and overexpression of the cyclin D1 gene (CCND1) might thus represent a genetic lesion inducing hormone-independent growth of transformed cells. Indeed, cyclin D1 overexpression has been found in up to 50% of primary breast cancers, and in about one-third of these cases, this is linked to amplification of the 11q13 chromosomal region, which also includes the CCND1 gene. These tumors are predominantly estrogen receptor-positive, and for this reason, these patients are often selected for adjuvant antiestrogen therapy. No information is available, however, as to whether cyclin D1 overexpression due to gene amplification might interfere with and reduce antiestrogen efficacy. This was investigated here by taking advantage of an experimental model that reproduces cyclin D1 overexpression resulting from increased CCND1 gene dosage in hormone-responsive human breast cancer cells. For this, MCF-7 cells stably transfected with a tet-inducible cyclin D1 expression vector were tested for their in vitro response to steroidal (ICI 182,780) and nonsteroidal (trans-4-hydroxytamoxifen) antiestrogens under condition of low (endogenous only) or high (exogenous) cyclin D1 levels. Results show that although cyclin D1 overexpression seems to interfere with the early cell cycle effects of antiestrogens, it does not prevent their cytostatic actions, so that growth of cyclin-overexpressing MCF-7 cells is still efficiently inhibited in vitro by these drugs.

¹ Supported by Associazione Italiana per la Ricerca sul Cancro, Consiglio Nazionale delle Ricerche 97.04417.CT14, Ministero per l'Università e la Ricerca Scientifica e Tecnologica (fondo 40% e 60%) of Italy, and Grant 97–143 from the Netherlands Cancer Foundation.

² To whom requests for reprints should be addressed, at Istituto di Patologia Generale e Oncologia, Facoltà di Medicina e Chirurgia, Seconda Università di Napoli, Larghetto S. Aniello a Caponapoli, 2, I-80138 Naples, Italy. Phone: 39-81-566-5671; Fax: 39-81-566-5695; E-mail: a.weisz@area.ba.cnr.it.

Received 9/26/97. Accepted 1/13/98.

This article has been cited by other articles:

				Y. Ishii, S. Waxman, and D. Germain Tamoxifen Stimulates the Growth of Cyclin D1-Overexpressing Breast Cancer Cells by Promoting the Activation of Signal Transducer and Activator of Transcription 3 Cancer Res., February 1, 2008; 68(3): 852 - 860. [Abstract] [Full Text] [PDF]

				J. S Lewis, T J Thomas, R. G Pestell, C. Albanese, M. A Gallo, and T. Thomas Differential effects of 16{alpha}-hydroxyestrone and 2-methoxyestradiol on cyclin D1 involving the transcription factor ATF-2 in MCF-7 breast cancer cells J. Mol. Endocrinol., February 1, 2005; 34(1): 91 - 105. [Abstract] [Full Text] [PDF]

				L. Cicatiello, R. Addeo, A. Sasso, L. Altucci, V. B. Petrizzi, R. Borgo, M. Cancemi, S. Caporali, S. Caristi, C. Scafoglio, et al. Estrogens and Progesterone Promote Persistent CCND1 Gene Activation during G1 by Inducing Transcriptional Derepression via c-Jun/c-Fos/Estrogen Receptor (Progesterone Receptor) Complex Assembly to a Distal Regulatory Element and Recruitment of Cyclin D1 to Its Own Gene Promoter Mol. Cell. Biol., August 15, 2004; 24(16): 7260 - 7274. [Abstract] [Full Text] [PDF]

				R. Hui, G. L. Finney, J. S. Carroll, C. S. L. Lee, E. A. Musgrove, and R. L. Sutherland Constitutive Overexpression of Cyclin D1 but not Cyclin E Confers Acute Resistance to Antiestrogens in T-47D Breast Cancer Cells Cancer Res., December 1, 2002; 62(23): 6916 - 6923. [Abstract] [Full Text] [PDF]

				A. J. Skildum, S. Mukherjee, and S. E. Conrad The Cyclin-dependent Kinase Inhibitor p21WAF1/Cip1 Is an Antiestrogen-regulated Inhibitor of Cdk4 in Human Breast Cancer Cells J. Biol. Chem., February 8, 2002; 277(7): 5145 - 5152. [Abstract] [Full Text] [PDF]

				E. A. Musgrove, L.-J. K. Hunter, C. S. L. Lee, A. Swarbrick, R. Hui, and R. L. Sutherland Cyclin D1 Overexpression Induces Progestin Resistance in T-47D Breast Cancer Cells Despite p27Kip1 Association with Cyclin E-Cdk2 J. Biol. Chem., December 7, 2001; 276(50): 47675 - 47683. [Abstract] [Full Text] [PDF]

				B. Perillo, A. Sasso, C. Abbondanza, and G. Palumbo 17beta -Estradiol Inhibits Apoptosis in MCF-7 Cells, Inducing bcl-2 Expression via Two Estrogen-Responsive Elements Present in the Coding Sequence Mol. Cell. Biol., April 15, 2000; 20(8): 2890 - 2901. [Abstract] [Full Text]

				E. K. Lobenhofer, G. Huper, J. D. Iglehart, and J. R. Marks Inhibition of Mitogen-activated Protein Kinase and Phosphatidylinositol 3-Kinase Activity in MCF-7 Cells Prevents Estrogen-induced Mitogenesis Cell Growth Differ., February 1, 2000; 11(2): 99 - 110. [Abstract] [Full Text]

				F. S. Kenny, R. Hui, E. A. Musgrove, J. M.W. Gee, R. W. Blamey, R. I. Nicholson, R. L. Sutherland, and J. F. R. Robertson Overexpression of Cyclin D1 Messenger RNA Predicts for Poor Prognosis in Estrogen Receptor-positive Breast Cancer Clin. Cancer Res., August 1, 1999; 5(8): 2069 - 2076. [Abstract] [Full Text] [PDF]

				O. Zach, H. Kasparu, O. Krieger, W. Hehenwarter, M. Girschikofsky, and D. Lutz Detection of Circulating Mammary Carcinoma Cells in the Peripheral Blood of Breast Cancer Patients Via a Nested Reverse Transcriptase Polymerase Chain Reaction Assay for Mammaglobin mRNA J. Clin. Oncol., July 1, 1999; 17(7): 2015 - 2015. [Abstract] [Full Text] [PDF]