Abstract
Recent advances in the understanding of cell cycle control by cyclins and cyclin-dependent kinases provide a basis for delineating the molecular mechanisms of proliferation control by steroids and the development and progression of hormone-dependent cancers. Cyclin D1 is necessary, rate-limiting and sufficient for G1 progression in breast cancer cells and regulation of cyclin D1 expression or function is an early response to steroid and steroid antagonist regulation of proliferation. The cyclin D1 gene is amplified in ∼15%, and its product overexpressed in 40–50%, of primary breast carcinomas. The strong evidence that cyclin D1 plays a major role in cell cycle control in breast epithelial cells suggests that its deregulated expression may have effects on disease progression and phenotype including sensitivity to endocrine therapies.
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B. Henderson, R. Ross, and L. Bernstein (1988). Estrogens as a cause of human cancer: the Richard and Hinda Rosenthal Foundation Award lecture.Cancer Res. 48:246–253.
C. J. Sherr (1994). G1 phase progression: cycling on cue.Cell 79:551–555.
T. Hunter and J. Pines (1994). Cyclins and cancer II: cyclin D and CDK inhibitors come of age.Cell 79:573–582.
V. Baldin, J. Lukas, M. J. Marcote, M. Pagano, and G. Draetta (1993). Cyclin D1 is a nuclear protein required for cell cycle progression in G1.Genes Dev. 7:812–821.
D. E. Quelle, R. A. Ashmun, S. A. Shurtleff, J.-y. Kato, D. Bar-Sagi, M. F. Roussel, and C. J. Sherr (1993). Overexpression of mouse D-type cyclins accelerates G1 phase in rodent fibroblasts.Genes Dev. 7:1559–1571.
D. Resnitzky, M. Gossen, H. Bujard, and S. I. Reed (1994). Acceleration of the G1/S phase transition by expression of cyclins D1 and E with an inducible system.Mol. Cell. Biol. 14:1669–1679.
E. A. Musgrove, C. S. L. Lee, M. F. Buckley, and R. L. Sutherland (1994). Cyclin D1 induction in breast cancer cells shortens G1 and is sufficient for cells arrested in G1 to complete the cell cycle.Proc. Natl. Acad. Sci. U.S.A. 91:8022–8026.
R. A. Weinberg (1995). The retinoblastoma protein and cell cycle control.Cell 81:323–330.
E. A. Musgrove, B. Sarcevic, and R. L. Sutherland (1995). Inducible expression of cyclin D1 in T-47D human breast cancer cells is sufficient for CDK2 activation and pRB hyperphosphorylation.J. Cell Biochem. (in press).
D. Resnitzky and S. I. Reed (1995). Different roles for cyclins D1 and E in regulation of the G1-to-S transition.Mol. Cell. Biol. 15:3463–3469.
J. Lukas, H. Müller, J. Bartkova, D. Spitkovsky, A. A. Kjerulff, P. Jansen-Dürr, M. Strauss, and J. Bartek (1994). DNA tumor virus oncoproteins and retinoblastoma gene mutations share the ability to relieve the cell's requirement for cyclin D1 function in G1.J. Cell Biol. 125:625–638.
D. O. Morgan (1995). Principles of CDK regulation.Nature 374:131–134.
C. J. Sherr and J. M. Roberts (1995). Inhibitors of mammalian G1 cyclin-dependent kinases.Genes Dev. 9:1149–1163.
O. Aprelikova, Y. Xiong, and E. T. Liu (1995). Both p16 and p21 families of cyclin-dependent kinase (CDK) inhibitors block the phosphorylation of cyclin-dependent kinases by the CDK-activating kinase.J. Biol. Chem. 270:18195–18197.
E. A. Musgrove and R. L. Sutherland (1994). Cell cycle control by steroid hormones. In M. G. Parker (ed.),Seminars in Cancer Biology, Academic Press, London,5:381–389.
C. K. W. Watts, N. R. C. Wilcken, J. A. Hamilton, K. J. E. Sweeney, E. A. Musgrove, and R. L. Sutherland (1995). Mechanisms of antiestrogen, progestin/antiprogestin and retinoid inhibition of cell cycle progression in breast cancer cells. In J. P. Pasqualini and B. S. Katzenellenbogen (eds.),Hormone-Dependent Cancers. Molecular and Cellular Endocrinology, Marcel Dekker, New York, pp 119–140.
T. Motokura, K. Keyomarsi, H. M. Kronenberg, and A. Arnold (1992). Cloning and characterization of human cyclin D3, a cDNA closely related in sequence to thePRAD1/cyclin D1 proto-oncogene.J. Biol. Chem. 267:20412–20415.
K. Keyomarsi and A. B. Pardee (1993). Redundant cyclin overexpression and gene amplification in breast cancer cells.Proc. Natl. Acad. Sci. U.S.A. 90:1112–1116.
E. A. Musgrove, J. A. Hamilton, C. S. L. Lee, K. J. E. Sweeney, C. K. W. Watts, and R. L. Sutherland (1993). Growth factor, steroid and steroid antagonist regulation of cyclin gene expression associated with changes in T-47D human breast cancer cell cycle progression.Mol. Cell. Biol. 13:3577–3587.
J. Gong, B. Ardelt, F. Traganos, and Z. Darzynkiewicz (1994). Unscheduled expression of cyclin B1 and cyclin E in several leukemic and solid tumor cell lines.Cancer Res. 54:4285–4288.
C. K. W. Watts, K. J. E. Sweeney, A. Warlters, E. A. Musgrove, and R. L. Sutherland (1994). Antiestrogen regulation of cell cycle progression and cyclin D1 gene expression in MCF-7 human breast cancer cells.Breast Cancer Res. Treat. 31:95–105.
C. K. W. Watts, A. Brady, B. Sarcevic, A. deFazio, E. A. Musgrove, and R. L. Sutherland (1995). Antiestrogen inhibition of cell cycle progression in breast cancer cells is associated with inhibition of cyclin-dependent kinase activity and decreased retinoblastoma protein phosphorylation.Mol. Endocrinol. 9:1804–1813.
N. R. C. Wilcken, B. Sarcevic, E. A. Musgrove, and R. L. Sutherland (1995). Differential effects of retinoids and antiestrogens on cell cycle progression and cell cycle regulatory genes in human breast cancer cells.Cell Growth Diff. (in press).
L. Xu, D. Sgroi, C. J. Sterner, R. L. Beauchamp, D. M. Pinney, S. Keel, K. Ueki, J. L. Rutter, A. J. Buckler, D. N. Louis, J. F. Gusella, and V. Ramesh (1994). Mutational analysis ofCDKN2 (MTS1/p16ink4) in human breast carcinomas.Cancer Res. 54:5262–5264.
E. A. Musgrove, R. Lilischkis, A. L. Cornish, C. S. L. Lee, V. Setlur, R. Seshadri, and R. L. Sutherland (1995). Expression of the cyclin-dependent kinase inhibitors p16INK4, p15INK4B and p21WAF1/CIP1 in human breast cancer.Int. J. Cancer 63:584–591.
J. Bartkova, J. Lukas, H. Müller, D. Lützhøft, M. Strauss, and J. Bartek (1994). Cyclin D1 protein expression and function in human breast cancer.Int. J. Cancer 57:353–361.
O. W. Prall, B. Sarcevic, E. A. Musgrove, C. K. W. Watts, and R. L. Sutherland. Estrogen regulation of cell cycle progression and CDK function in human breast cancer cells. (submitted).
D. Dubik, T. C. Dembinski, and R. P. C. Shiu (1987). Stimulation of c-myc oncogene expression associated with estrogen-induced proliferation of human breast cancer cells.Cancer Res. 47:6517–6521.
J. I. Daksis, R. Y. Lu, L. M. Facchini, W. W. Marhin, and L. J. Z. Penn (1994).Myc induces cyclin D1 expression in the absence ofde novo protein synthesis and links mitogen-stimulated signal transduction to the cell cycle.Oncogene 9:3635–3645.
E. A. Musgrove, C. S. L. Lee, and R. L. Sutherland (1991). Progestins both stimulate and inhibit breast cancer cell cycle progression while increasing expression of transforming growth factor α, epidermal growth factor receptor, c-fos and c-myc genes.Mol. Cell. Biol. 11:5032–5043.
T. C. Wang, R. D. Cardiff, L. Zukerberg, E. Lees, A. Arnold, and E. V. Schmidt (1994). Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice.Nature 369:669–671.
P. Sicinski, J. Liu Donaher, S. B. Parker, T. Li, A. Fazeli, H. Gardner, S. Z. Haslam, R. B. Bronson, S. J. Elledge, and R. A. Weinberg (1995). Cyclin D1 provides a link between development and oncogenesis in the retina and breast.Cell 82:621–630.
C. L. Clarke and R. L. Sutherland (1990). Progestin regulation of cellular proliferation.Endocrinol. Rev. 11:266–302.
E. A. Musgrove, C. S. L. Lee, A. L. Cornish, and R. L. Sutherland. Progestin antagonist inhibition of cell cycle progression in T-47D breast cancer cells is preceded by induction of the CDK inhibitor p21. (submitted).
T. K. Said, L. Lou, and D. Medina (1995). Mouse mammary hyperplasias and neoplasias exhibit different patterns of cyclins D1 and D2 binding to Cdk4.Carcinogenesis (in press).
V. Fantl, R. Smith, S. Brookes, C. Dickson, and G. Peters (1993). Chromosome 11q13 abnormalities in human breast cancer.Cancer Surv. 18:77–93.
G. Peters, V. Fantl, R. Smith, S. Brookes, and C. Dickson (1995). Chromosome 11q13 markers and D-type cyclins in breast cancer.Breast Cancer Res. Treat. 33:125–135.
M. F. Buckley, K. J. E. Sweeney, J. A. Hamilton, R. L. Sini, D. L. Manning, R. I. Nicholson, A. deFazio, C. K. W. Watts, E. A. Musgrove, and R. L. Sutherland (1993). Expression and amplification of cyclin genes in human breast cancer.Oncogene 8:2127–2133.
C. Gillett, V. Fantl, R. Smith, C. Fisher, J. Bartek, C. Dickson, D. Barnes, and G. Peters (1994). Amplification and overexpression of cyclin D1 in breast cancer detected by immunohistochemical staining.Cancer Res. 54:1812–1817.
J. Bartkova, J. Lukas, M. Strauss, and J. Bartek (1995). Cyclin D1 oncoprotein aberrantly accumulates in malignancies of diverse histogenesis.Oncogene 10:775–778.
E. M. J. J. Berns, J. G. M. Klijn, I. L. van Staveren, H. Portengen, E. Noordegraaf, and J. A. Foekens (1992). Prevalence of amplification of the oncogenes c-myc, HER2/neu, andint-2 in one thousand human breast tumors: correlation with steroid receptors.Eur. J. Cancer 28:697–700.
R. Seshadri, C. S. L. Lee, R. Hui, K. McCaul, D. J. Horsfall, and R. L. Sutherland. Cyclin D1 amplification is not associated with poor prognosis in primary breast cancer. (submitted).
H. Tsuda, S. Hirohashi, Y. Shimosato, T. Hirota, S. Tsugane, H. Yamamoto, N. Miyajima, K. Toyoshima, T. Yamamoto, J. Yokota, T. Yoshida, H. Sakamoto, M. Terada, and T. Sugimura (1989). Correlation between long-term survival in breast cancer patients and amplification of two putative oncogene-coamplification units:hst-1/int-2 and c-erbB2/ear-1.Cancer Res. 49:3104–3108.
A. Borg, H. Sigurdsson, G. M. Clark, M. Ferno, S. A. Fuqua, H. Olson, D. Kilander, and W. L. McGuire (1991). Association ofINT2/HST coamplification in primary breast cancer with hormone-dependent phenotype and poor prognosis.Br. J. Cancer 63:136–142.
E. Schuuring, E. Verhoeven, H. van Tinteren, J. L. Peterse, B. Nunnink, F. B. J. M. Thunnissen, P. Devilee, C. J. Cornelisse, M. J. van de Vijver, W. J. Mooi, and R. J. A. M. Michalides (1992). Amplification of genes within the chromosome 11q13 region is indicative of poor prognosis in patients with operable breast cancer.Cancer Res. 52:5229–5234.
J. A. Henry, C. Hennessy, D. L. Levett, T. W. J. Lennard, B. R. Westley, and F. E. B. May (1993).int-2 amplification in breast cancer: association with decreased survival and relationship to amplification of c-erbB-2 and c-myc.Int. J. Cancer 53:774–780.
E. M. J. J. Berns, J. A. Foekens, I. L. van Staveren, M. P. Look, W. L. J. van Putten, H. Portengen, M. Meijer-vanGelder, and J. G. M. Klijn. c-MYC gene amplification is preferable to amplification ofHER2/NEU or 11q13 regarding prognostic (and predictive) information: an analysis on 663 breast cancer patients. (submitted).
K. Keyomarsi, N. O'Leary, G. Molnar, E. Lees, H. J. Fingert, and A. B. Pardee (1994). Cyclin E, a potential prognostic marker for breast cancer.Cancer Res. 54:380–385.
T. K. Said and D. Medina (1995). Cell cyclins and cyclin dependent kinase activities in mouse mammary tumor development.Carcinogenesis 16:823–830.
J. Lukas, J. Bartkova, M. Welcker, O. W. Petersen, G. Peters, M. Strauss, and J. Bartek (1995). Cyclin D2 is a moderately oscillating nucleoprotein required for G1 phase progression in specific cell types.Oncogene 10:2125–2134.
A. Kamb (1995). Cell-cycle regulators and cancer.Trends Genet. 11:136–140.
A. Okamoto, D. J. Demetrick, E. A. Spillare, K. Hagiwara, S. P. Hussian, W. P. Bennett, K. Forrester, B. Gerwin, M. Serrano, D. H. Beach, and C. C. Harris (1994). Mutations and altered expression of p16INK4 in human cancer.Proc. Natl. Acad. Sci. U.S.A. 91:11045–11049.
A. Kamb, N. A. Gruis, J. Weaver-Feldhaus, Q. Liu, K. Harshman, S. V. Tavtigian, L. J. Old, E. Stockert, R. S. Day, B. Johnson, and M. H. Skolnick (1994). A cell cycle regulator potentially involved in genesis of many tumor types.Science 264:436–440.
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Musgrove, E.A., Hui, R., Sweeney, K.J.E. et al. Cyclins and breast cancer. J Mammary Gland Biol Neoplasia 1, 153–162 (1996). https://doi.org/10.1007/BF02013639
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DOI: https://doi.org/10.1007/BF02013639