Clinical significance of cyclin D1 expression in patients with node-positive breast carcinoma treated with adjuvant therapy.

BACKGROUND Experimental and clinical studies suggest that cyclin D1 is involved in transformation and tumour progression. However, there is little and contradictory data on the clinical significance of cyclin D1 in human invasive breast carcinoma. PATIENTS AND METHODS We investigated whether the determination of cyclin D1 has prognostic value in a series of 180 patients with node-positive breast carcinoma and treated with adjuvant therapy with a median follow-up exceeding 6 years. We assessed cyclin D1 expression using the CDS-6 monoclonal antibody and a highly sensitive immunohistochemical technique. RESULTS We found that most of the evaluable tumours (117 of 167; 70.1%) presented nuclear cyclin D1 staining and that its expression was significantly associated with both the hormone receptors (P = 0.009 and P = 0.005 for ER and PgR, respectively). Furthermore, 29 (17%) of 167 tumours had a weak (15 cases) or strong (9 cases) cytoplasmic cyclin D1 staining. In a subgroup of cases we also studied the amplification of the cyclin D1 gene and a moderate agreement between cyclin D1 nuclear overexpression assessed immunohistochemically and the gene amplification was found. In univariate analysis, cyclin D1 nuclear positivity was significantly associated with improved 6-year relapse-free survival (RFS) (P = 0.004), but not with overall survival (OS) (P = 0.12). The results of the Cox multivariate analysis (final model) indicate that cyclin D1 expression (P = 0.0049) as well as the number of involved nodes (P < 0.001) and tumour size (P = 0.036) are significant prognostic indicators for RFS. Only the number of involved nodes retained significance (P < 0.001) for OS in our series. The joint assessment of the variables considered in the final model of the multivariate analyses had a moderate prognostic capability as determined using the Harrell c statistic (c = 0.66 and 0.64 for RFS and OS, respectively). CONCLUSIONS The patients with node-positive breast cancer who have a higher likelihood of gaining benefit from adjuvant therapy are those with tumours with cyclin D1 nuclear expression, small size and less than 3 metastatic nodes. Further studies are needed to verify the prognostic value of cyclin D1 in relation to different adjuvant treatments and to deepen the biological pathways that regulate its activation/ suppression in human breast carcinoma.

[1]  S. Fox,et al.  Determination of angiogenesis adds information to estrogen receptor status in predicting the efficacy of adjuvant tamoxifen in node-positive breast cancer patients. , 1996, Clinical cancer research : an official journal of the American Association for Cancer Research.

[2]  E. Schuuring,et al.  Expression of cyclin D1 and EMS1 in bladder tumours; relationship with chromosome 11q13 amplification. , 1996, Oncogene.

[3]  J. Peterse,et al.  A clinicopathological study on overexpression of cyclin D1 and of p53 in a series of 248 patients with operable breast cancer. , 1996, British Journal of Cancer.

[4]  D. Betticher Cyclin D1, another molecule of the year? , 1996, Annals of oncology : official journal of the European Society for Medical Oncology.

[5]  W. Ryder,et al.  Prognostic significance of CCND1 (cyclin D1) overexpression in primary resected non-small-cell lung cancer. , 1996, British Journal of Cancer.

[6]  B. Jennings,et al.  Cyclin D1 amplification and expression in human breast carcinoma: correlation with histological prognostic markers and oestrogen receptor expression , 1996, Clinical molecular pathology.

[7]  B. Gallie,et al.  Loss of Rb and Myc activation co-operate to suppress cyclin D1 and contribute to transformation. , 1996, Oncogene.

[8]  J. Bartek,et al.  Unrestricted cell cycling and cancer , 1995, Nature Medicine.

[9]  M. Merino,et al.  Overexpression of cyclin D mRNA distinguishes invasive and in situ breast carcinomas from non-malignant lesions , 1995, Nature Medicine.

[10]  J. Concato,et al.  Importance of events per independent variable in proportional hazards regression analysis. II. Accuracy and precision of regression estimates. , 1995, Journal of clinical epidemiology.

[11]  X. Chen,et al.  p53, through p21 (WAF1/CIP1), induces cyclin D1 synthesis. , 1995, Cancer research.

[12]  B. Angus,et al.  Determination of the prognostic value of cyclin D1 overexpression in breast cancer. , 1995, Oncogene.

[13]  S. Elledge,et al.  Cyclin D1 provides a link between development and oncogenesis in the retina and breast , 1995, Cell.

[14]  X. Graña,et al.  Cell cycle control in mammalian cells: role of cyclins, cyclin dependent kinases (CDKs), growth suppressor genes and cyclin-dependent kinase inhibitors (CKIs). , 1995, Oncogene.

[15]  M. Barbareschi,et al.  Tumor angiogenesis predicts clinical outcome of node-positive breast cancer patients treated with adjuvant hormone therapy or chemotherapy. , 1995, The cancer journal from Scientific American.

[16]  R. Gopalkrishnan,et al.  The role of p53 in coordinated regulation of cyclin D1 and p21 gene expression by the adenovirus E1A and E1B oncogenes. , 1995, Oncogene.

[17]  P. Atadja,et al.  Overexpression of cyclin D1 blocks proliferation of normal diploid fibroblasts. , 1995, Experimental cell research.

[18]  I. Schieren,et al.  Stable overexpression of cyclin D1 in a human mammary epithelial cell line prolongs the S-phase and inhibits growth. , 1995, Oncogene.

[19]  J. Bartek,et al.  Cyclin D1 oncoprotein aberrantly accumulates in malignancies of diverse histogenesis. , 1995, Oncogene.

[20]  G. Peters,et al.  Lack of cyclin D‐Cdk complexes in Rb‐negative cells correlates with high levels of p16INK4/MTS1 tumour suppressor gene product. , 1995, The EMBO journal.

[21]  D. Reisman,et al.  Transforming growth factor-beta 1 inhibits cyclin D1 expression in intestinal epithelial cells. , 1995, Oncogene.

[22]  L. M. Facchini,et al.  Myc induces cyclin D1 expression in the absence of de novo protein synthesis and links mitogen-stimulated signal transduction to the cell cycle. , 1994, Oncogene.

[23]  C. Sherr G1 phase progression: Cycling on cue , 1994, Cell.

[24]  A. Klein-Szanto,et al.  Immunohistochemistry of cyclin D1 in human breast cancer. , 1994, American journal of clinical pathology.

[25]  R. Sutherland,et al.  Cyclin D1 induction in breast cancer cells shortens G1 and is sufficient for cells arrested in G1 to complete the cell cycle. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[26]  Jiri Bartek,et al.  Cyclin D1 protein expression and function in human breast cancer , 1994, International journal of cancer.

[27]  J. Bartek,et al.  Amplification and overexpression of cyclin D1 in breast cancer detected by immunohistochemical staining. , 1994, Cancer research.

[28]  N. Weidner,et al.  Tumor microvessel density, p53 expression, tumor size, and peritumoral lymphatic vessel invasion are relevant prognostic markers in node-negative breast carcinoma. , 1994, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[29]  S. Estus,et al.  Analysis of cell cycle-related gene expression in postmitotic neurons: Selective induction of cyclin D1 during programmed cell death , 1994, Neuron.

[30]  S. Reed,et al.  Altered regulation of G1 cyclins in senescent human diploid fibroblasts: accumulation of inactive cyclin E-Cdk2 and cyclin D1-Cdk2 complexes. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[31]  J. A. Hamilton,et al.  Expression and amplification of cyclin genes in human breast cancer. , 1993, Oncogene.

[32]  J. A. Hamilton,et al.  Growth factor, steroid, and steroid antagonist regulation of cyclin gene expression associated with changes in T-47D human breast cancer cell cycle progression. , 1993, Molecular and cellular biology.

[33]  M. J. van de Vijver,et al.  Amplification of genes within the chromosome 11q13 region is indicative of poor prognosis in patients with operable breast cancer. , 1992, Cancer research.

[34]  Richard A. Ashmun,et al.  Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle , 1991, Cell.

[35]  G. Peters,et al.  Gene amplification on chromosome band 11q13 and oestrogen receptor status in breast cancer. , 1990, European journal of cancer.

[36]  C. Theillet,et al.  Proto-oncogene amplification and human breast tumor phenotype. , 1989, Oncogene.

[37]  F. Harrell,et al.  Evaluating the yield of medical tests. , 1982, JAMA.

[38]  N. Blin,et al.  A general method for isolation of high molecular weight DNA from eukaryotes. , 1976, Nucleic acids research.

[39]  B. Fisher,et al.  The pathology of invasive breast cancer A Syllabus Derived from Findings of the National Surgical Adjuvant Breast Project (Protocol No. 4) , 1975, Cancer.

[40]  A. Pardee,et al.  A restriction point for control of normal animal cell proliferation. , 1974, Proceedings of the National Academy of Sciences of the United States of America.

[41]  Jacob Cohen A Coefficient of Agreement for Nominal Scales , 1960 .

[42]  H. Bloom,et al.  Histological Grading and Prognosis in Breast Cancer , 1957, British Journal of Cancer.

[43]  I. Weinstein,et al.  Overexpression of cyclin D1 enhances gene amplification. , 1996, Cancer research.

[44]  J. A. Hamilton,et al.  Expression and regulation of cyclin genes in breast cancer. , 1995, Acta oncologica.

[45]  Dulic,et al.  老化ヒト二倍体線維芽細胞におけるG1サイクリン調節の変化 不活性サイクリンE‐Cdk2及びサイクリンD1‐Cdk2複合体 , 1993 .