© 2007 Foundation for Promotion of Cancer Research
Expression of c-erbB2, cyclin D1 and Estrogen Receptor and their Clinical Implications in the Invasive Ductal Carcinoma of the Breast
1 Department of Hospital Pathology
2 Department of Surgery
3 Department of Preventive Medicine
4 Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
For reprints and all correspondence: Gyeongsin Park, Department of Hospital Pathology, College of Medicine, Catholic University of Korea, St Mary's Hospital, 62 Youido-dong, Young Dung Po-gu, Seoul 150-713, South Korea. E-mail address: klee{at}catholic.ac.kr
Received February 20, 2007; accepted April 27, 2007
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Background: C-erbB2 and estrogen receptors (ER) are well known for their cell proliferative capacity. Cyclin D1 is a major downstream target of both c-erbB2 and ER. This study was designed to analyze the expression of c-erbB2, cyclin D1 and ER and their prognostic implications in invasive ductal carcinoma of the breast.
Methods: The c-erbB2 status was evaluated by fluorescence in situ hybridization and immunohistochemistry (IHC) and cyclin D1 and ER were evaluated by IHC in 333 invasive breast cancer specimens.
Results: The results of FISH and IHC for c-erbB2 showed 86.7% concordance. The overexpression of c-erbB2 was associated with the high expression of cyclin D1 and the negative expression of ER (P < 0.01 for both). The high expression of cyclin D1 was associated with the positive expression of ER (P < 0.01). When the group of patients who overexpressed c-erbB2 were analyzed, the patients with the low expression of cyclin D1 showed a significantly higher mortality than those with the high expression of cyclin D1 (RR = 3.2; 95% CI, 1.6–6.6). When the group of the high cyclin D1 expression was analyzed, the patients with negative expression of ER showed a significantly higher mortality than those with the positive expression of ER (RR = 2.1; 95% CI, 1.1–3.8).
Conclusions: Higher expression of cyclin D1 was associated with better prognosis in patients with c-erbB2 overexpression, and positive expression of ER was associated with better prognosis in patients with high cyclin D1 expression.
Key Words: breast cancer • c-erbB2 • cyclin D1 • estrogen receptor
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Invasive ductal carcinoma (IDC), the most common type of breast cancer, is a heterogeneous group of tumors that fail to exhibit sufficient characteristics to achieve classification as a specific histological type (1). The prognostic or predictive factors currently in use do not provide sufficient information to allow accurate individual risk assessment and treatment planning, emphasizing the need for additional prognostic and therapeutic factors (2,3).
C-erbB2 is a transmembrane glycoprotein involved in cell growth control that is overexpressed in approximately 25–30% of breast cancers. It plays an important role in the development of breast cancer. Trastuzumab, a recombinant monoclonal antibody targeting the c-erbB2 protein, has been shown to be effective in treating the breast cancer patients with c-erbB2 overexpression, giving a 20% response rate (1,4). Estrogen receptor (ER) status has been used in predicting the response to adjuvant tamoxifen therapy for more than 20 years and has remained the most powerful molecular marker for treatment decision. ER-positive IDCs have a 40–70% response rate in tamoxifen treatment (5). It is far from clear, however, what makes the difference between responders and non-responders towards therapeutic agents such as Trastuzumab or tamoxifen.
A critical target of the c-erbB2 functions in breast cancer is cyclin D1-cdk4/6 interactions (6). Cyclin D1 is also one of the key mediators of the proliferative effects of estrogen and the net result of this pathway is phosphorylation of pRb (7). It has been suggested that cyclin D1 can bind directly to and activate estrogen receptors independently from estrogen (8).
In the present study, we tried to evaluate the association and the prognostic implications of c-erbB2 status, cyclin D1 expression and ER expression using fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC).
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Patients and Tissue Samples
We analyzed the tissues from 333 patients who underwent breast surgery and were newly diagnosed histologically with primary IDC between January 1990 and December 2000 at Kangnam St Mary's Hospital, the Catholic University of Korea. Carcinoma in situ and other precancerous lesions such as ductal hyperplasia were excluded.
Tissue Array
In order to construct the tissue microarray block, 3 mm-sized core biopsies were taken from viable morphologically representative areas of the paraffin-embedded tumor tissues and were assembled on a recipient paraffin block containing 30 biopsies. This was carried out using a precision instrument (Micro Digital Co., Gunpo-si, Gyeonggi-do, Korea). After construction, 5 µm sections were cut and the histology was verified by hematoxylin–eosin staining.
Fluorescence in situ Hybridization of c-erbB2
FISH was performed using PathVysionTM HER2/CEN probe (Vysis Inc., Downers Grove, IL, USA). The c-erbB2 gene to chromosome 17 centromere ratio was measured in at least 60 nuclei from the tumor cells, and an average score was taken. More than two copies of c-erbB2 for each chromosome 17 was considered to be a positive sign for c-erbB2 gene amplification.
Immunohistochemistry
Five-micrometer sections of the paraffin-embedded tissue arrays were deparaffinized, rehydrated in a graded series of alcohol and microwave-treated for 10 min in a citrate buffer (pH 6.0). The endogenous peroxidase activity was blocked using 0.3% hydrogen peroxide. The tissue arrays were processed in an automatic IHC staining machine using standard procedures (Lab Vision autostainer, Lab Vision Co., Fremont, CA, USA) with a DAKO ChemMateTM EnVisionTM system (DAKO, Carpinteria, CA, USA). The following antibodies were used: c-erbB2 (1:200, polyclonal, DAKO), cyclin D1 (1:50, P2D11F11, Novocastra Laboratories Ltd, Newcastle upon Tyne, UK) and ER (1:200, 1D5, DAKO). The sections were visualized with 3-3'-diaminobenzidine (DAB) and counterstained with Mayer hematoxylin.
The c-erbB2 expression level was classified into four groups according to the scoring guidelines of the HercepTestTM (9). Briefly, a score of 0 was given to those specimens showing no staining, or membrane staining in <10% of the tumor cells. A score of 1+ was given to a specimen showing faint or barely perceptible membrane staining in >10% of tumor cells. A score of 2+ was given to specimens showing weak to moderate complete membrane staining in >10% of tumor cells. A score of 3+ was given to specimens showing strong complete membrane staining in >10% of tumor cells. The cyclin D1 expression levels were determined semiquantitatively based on the positive nuclear staining fraction of tumor cells (grade 0 = no stating, grade 1 = 1–5%; grade 2+ = 6–10%; grade 3+ = 11–25%; grade 4+ = 26–50%; grade 5+ = 51–100%). The ER expression level was estimated based on the fraction of tumor cells showing positive nuclear staining (grade 0 = 0–10%; grade 1+ = 11–25%; grade 2+ = 26–50%; grade 3+ = 51–75%; grade 4+ = 76–100%).
Statistical Methods
All statistical analyses were performed using the SAS program (version 8.0) for Windows. The survival duration was defined as the time from surgery to death attributed to breast cancer. The association between FISH and IHC results and the clinicopathological variables were performed using the 
2 -test. Survival curves were plotted using the Kaplan and Meier method and statistical significance was determined by the log-rank test. Univariate analysis and multivariate survival analysis using the Cox proportional hazards model were performed. A P-value of <0.05 was considered significant.
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RESULTS |
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Characteristics of the Patients
The patients were all female and their ages at the time of the diagnosis ranged from 23 to 80 years (mean 49 years). One-hundred and fifteen patients were in menopausal state at the time of diagnosis and 207 patients were in pre-menopausal state. The tumor size ranged from 0.7 to 17 cm in the greatest dimension (mean 3.3 cm). Median length of follow-up was 57 months (range 1–162 months). Within the observation period, a total of 88 patients died due to cancer-related causes. Clinical characteristics of 333 patients are summarized in Table 1.
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The FISH and IHC for c-erbB2 and IHC for Cyclin D1 and ER
For FISH, the c-erbB2 gene status was non-amplified in 248 patients (74.5%), amplified in 82 (24.6%) and not interpretable in 3 (0.9%; Fig. 1A and B). For IHC analysis, the scores for c-erbB2 expression were 0 or 1+ in 217 patients (65.2%), 2+ in 38 (11.4%), and 3+ in 78 (23.4%; Fig. 1C and D). The FISH and IHC results for c-erbB2 showed 86.7% (
= 0.69) concordance when c-erbB2 scores of 2+ and 3+ were considered positive. The c-erbB2 status was determined primarily from the FISH results.
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The results of cyclinD1 were classified high and low expression using the median value as a cutoff value. The high expression of cyclin D1 was defined as grade 3 or more (>10%). Sixty-four percent (209 out of 327 cases) of the IDC cases showed the high expression of cyclin D1 (Fig. 1E). The positive expression of ER was defined as grade 1 or more (>10%) (10,11). The positive expression of ER was 63.6% (203 out of 319 cases; Fig. 1F).
Correlation between the c-erbB2, cyclin D1 and ER
The overexpression of c-erbB2 was associated with the high expression of cyclin D1 and the negative expression of ER (P < 0.01, each). The high expression of cyclin D1 was associated with the positive expression of ER (P < 0.01).
Association with the Clinicopathological Parameters
We tested for the correlation between the expression of c-erbB2, cyclin D1 and ER and clinicopathological parameters such as tumor size, lymph node metastasis, menstrual status and patient's age. The overexpression of c-erbB2 was associated with larger tumor size and axillary lymph node involvement (P = 0.03 and P = 0.02, respectively). The high expression of cyclin D1 was associated with smaller tumor size (P = 0.04; Table 2). The expression of cyclin D1 was not associated with lymph node metastasis, menstrual status or patient's age (P > 0.05, each). The expression of ER was not associated with the tumor size, lymph node metastasis, menstrual status or patient's age (P > 0.05, each). The prognostic value of cyclin D1 and c-erbB2 in combination was further analyzed. When the patients in the c-erbB2 overexpressing group were analyzed, those with the low expression of cyclin D1 showed a significantly higher mortality than those with high expression of cyclin D1 (RR = 3.2; 95% CI, 1.6–6.6). In the patients with no overexpression of c-erbB2, there was no significant difference in prognosis between the high cyclin D1 expressing group and the low cyclin D1 expressing group (P = 0.81; Fig. 2). The prognostic value of ER and cyclin D1 in combination was also analyzed. When patients in the high cyclin D1 expressing group were analyzed, those with negative expression of ER showed a significantly higher mortality than those with positive expression of ER (RR = 2.1; 95% CI, 1.1–3.8). In the patients with the low expression of cyclin D1, there was no significant difference in prognosis between the group with positive expression of ER and those with negative expression (P = 0.77; Fig. 3). In the ER positive group, there was no significant difference in prognosis between the high cyclin D1 expressing group and the low cyclin D1 expressing group (P = 0.34), while in the ER negative group, there was no significant difference in prognosis between the high cyclin D1 expressing group and the low cyclin D1 expressing group (P = 0.56). Univariate analysis demonstrated worse survival with overexpression of c-erbB2, the negative expression of ER, larger tumor size, lymph node metastasis and menopausal status, but not with high expression of cyclin D1 and patient's age (
50 vs >50; Table 1). Multivariate analysis showed that tumor size, lymph node metastasis, the overexpression of c-erbB2 and menstrual status are independent prognostic factors (Table 3).
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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In carcinogenesis, one of the important steps is to obtain proliferative capacity without external stimuli, usually as a consequence of oncogene activation; c-erbB2 and ER are well-known for their involvement in the cell proliferative activity. As a result of c-erbB2 overexpression, the G1 phase is shortened and cells enter into the S phase earlier, which leads to hyperproliferation. This was mediated by the up-regulation of cdk6 and cyclin D1 and E, and enhanced degradation and re-localization of p27 (6). The c-erbB2 overexpression in breast cancer is associated with a higher histological grade, reduced survival, lower responsiveness to methotrexate-based treatment regimens and hormone receptor modulators such as tamoxifen, and a higher responsiveness to doxorubicin-based regimens (1,2). Therefore, determining the c-erbB2 status is important for obtaining the appropriate prognostic and predictive data. In this study, c-erbB2 was overexpressed in 85 out of 333 cases (25.5%). The overexpression of c-erbB2 was shown to be associated with larger tumor size, lymph node metastasis and a poor survival by univariate analysis (P = 0.03, P = 0.02, P = <0.001, respectively).
Cyclin D1 is a major downstream target of erbB2-dependant signaling and intact cyclin D1 is important for the action of c-erbB2 (6). Lenferink et al. reported that activated c-erbB2 can increase cyclin D1 transcription through the Ras/MAPK pathway and activated c-erbB2 can inhibit cyclin D1 degradation through the PI3K/Akt pathway (12). In accordance with this concept, in present study overexpression of c-erbB2 was statistically significanttly associated with high expression of cyclin D1 (P = 0.003).
It has been reported that ER expression is associated with cyclin D1 overexpression (7,13–17). Cyclin D1 binds to the ER together with the cofactor SRC-1 and activates it in a ligand-independent manner (18,19), and estrogens activate cyclin D1 through increased transcription of cyclin D1 gene (20,21). In accordance with this concept, in the present study positive expression of ER showed statistically significant association with high expression of cyclinD1 (P = <0.001).
High expression of cyclin D1 shown by immunohistochemistry has been reported in 35–81% of breast carcinomas (22–24), which is in line with our result (64% of IDCs), and an amplification of the cyclin D1 gene was reported in 10–20% of breast carcinomas (25,26). Therefore, other mechanisms such as transcriptional activation of cyclin D1 gene are important for altered cyclin D1 expression level. There has been controversy in explaining the meaning of the cyclin D1 expression as a prognostic or predictive marker. Some studies have reported that cyclin D1 overexpression indicates a poor prognosis in breast cancer (27,28) and some have reported it to be of no prognostic significance (29,30), while others have reported that cyclin D1 overexpression is associated with a better prognosis in breast cancers (31,32). The present study showed no significant relationship between the expression of cyclin D1 and the survival outcome in patients with invasive breast cancer. Stendahl et al. suggested that, when no hormone therapy was involved, patients with breast cancers expressing high cyclin D1 levels had a better survival outcome than those with cyclin D1 low/moderate breast cancers, but cyclin D1 overexpression is a negative predictive factor for the response to tamoxifen in postmenopausal breast cancer patients (33). Jirström et al. also reported that amplification of CCND1 gene is a strong independent negative predictor of tamoxifen response in premenopausal breast cancer and a 6- to 9-fold higher relative risk of disease recurrence and death in CCND1-amplified tumors (34). Ahnström et al. reported that combined cyclin D1 and c-erbB2 overexpression among breast cancer patients is associated with a high rate of recurrence and suggested that cyclin D1 and c-erbB2 can cooperate to produce a more malignant tumor type with worse prognosis (35). In this study, among the patients with overexpression of c-erbB2, high expression of cyclin D1 showed a better survival than the low expression of cyclin D1. Our results appear to be paradoxical when considering the well-known function of cyclin D1, namely cell cycle regulation, initiating pRb phosphorylation and beginning the cascade of events that lead to DNA replication and cell division (36). However, in support of our interpretation, in our study there was no association between cyclin D1 expression and cell proliferation activity mirrored by Ki-67 LI (data not shown) and recently published studies showed that cyclin D1 may have diverse effects including antitumor effects. Cyclin D1 may be related to the induction of apoptosis and cellular growth inhibition (37). Cyclin D1 overexpressers led to an increased incidence of apoptosis after ionizing radiation or a treatment with various hydroxyurea or protein kinase C inhibitors in cell line studies (38–40).
Among the patients with the high expression of cyclin D1, those with positive expression of ER showed a better survival outcome than those with negative expression of ER. On the other hand, among the patients with the low expression of cyclin D1, there was no significant survival difference between the group of positive expression of ER and the group of negative expression. Similarly, Hwang et al. reported that tumors showing positive both for cyclin D1 and ER had a better survival than the tumors showing positive for either cyclin D1 or ER, or the tumors showing both negative for cyclin D1 and ER (22).
In conclusion, higher expression of cyclin D1 was associated with better prognosis in the c-erbB2 overexpressing patients, and the positive expression of ER was associated with better prognosis in patients with high cyclin D1 expressinon. However, this study has a limitation due to no treatment information and further studies are needed to clarify the function of cyclin D1 as a prognostic and/or predictive factor.
Conflict of interest statement
None declared.
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References |
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1 Tavassoli FA, Devilee P. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Breast and Female Genital Organs. (2003) Lyon: IARC Press. 13–21.
2 Hicks DG, Dawson A, Mattingly S, Crowe JP. The unmet clinical need for new molecular genetic markers in the prognosis and therapeutic management of breast cancer. Arch Pathol Lab Med (2005) 129:1372–4.[Web of Science][Medline]
3 Esteva FJ, Sahin AA, Cristofanilli M, Arun B, Hortobagyi GN. Molecular prognostic factors for breast cancer metastasis and survival. Semin Radiat Oncol (2002) 12:319–28.[CrossRef][Web of Science][Medline]
4 Kumar V, Abbas AK, Fusto N. The breast. In: Pathologic Basis of Disease (2004) 7th edn. Philadelphia, PA: Elsevier/Saunders. 1119–54.
5 Fitzgibbons PL, Page DL, Weaver D, Thor AD, Allred DC, Clark GM, et al. Prognostic factors in breast cancer. College of American pathologists consensus statement. Arch Pathol Lab Med (2000) 124:966–78.[Web of Science][Medline]
6 Timms JF, White SL, O'Hare MJ, Waterfield MD. Effects of erbB-2 overexpression on mitogenic signaling and cell cycle progression in human breast luminal epithelial cells. Oncogene (2002) 21:6573–86.[CrossRef][Web of Science][Medline]
7 Doisneau-Sixou SF, Sergio CM, Carroll JS, Hui R, Musgrove EA, Sutherland RL. Estrogen and antiestrogen regulation of cell cycle progression in breast cancer cells. Endocr Relat Cancer (2003) 10:179–86.[Abstract]
8 Neuman E, Ladha MH, Lin N, Upton TM, Miller SJ, DiRenzo J, et al. Cyclin D1 stimulation of estrogen receptor transcription activity independent of cdk4. Mol Cell Biol (1997) 17:5338–47.
9 Jacobs TW, Bown AM, Yaziji H, Barnes MJ, Shinitt SJ. Specificity of HercepTest in determining HER-2/neu status of breast cancer using the United States Food and Drug Administration-approved scoring system. J Clin Oncol (1999) 17:1983–7.
10 Pertschuk LP, Feldman JG, Kim YD, Braithwaite L, Schneider F, Braverman AS, et al. Estrogen receptor immunocytochemistry in paraffin embedded tissues with ER1D5 predicts breast cancer endocrine response more accurately than H222Sp gamma in frozen sections or cytosol-based ligand-binding assays. Cancer (1996) 77:2514–9.[CrossRef][Web of Science][Medline]
11 Reed W, Hannisdal E, Boehler PJ, Gundersen S, Host H, Nesland JM. The prognostic value of p53 and c-erb b-2 immunostaining is overrated for patients with lymph node negative breast carcinoma; a multivariate analysis of prognostic factors in 613 patients with a follow-up of 14–30 years. Cancer (2000) 88:804–13.[CrossRef][Web of Science][Medline]
12 Lenferink AE, Busse D, Flanagn WM, Yakes FM, Arteaga CL. ErbB2/neu kinase modulates cellular p27 (Kip1) and cyclin D1 through multiple signaling pathways. Cancer Res (2001) 61:6583–91.
13 Lebeau A, Unholzer A, Amann G, Kronawitter M, Bauerfeind I, Sendelhofert A, et al. EGFR, Her-2/neu, cyclin D1, p21 and p53 in correlation to cell proliferation and steroid hormone receptor status in ductal carcinoma in situ of the breast. Breast Cancer Res Treat (2003) 79:187–98.[CrossRef][Web of Science][Medline]
14 Spyratos F, Andrieu C, Vidaud D, Briffod M, Vidaud M, Lidereau R, et al. CCND1 mRNA overexpression is highly related to estrogen receptor positivity but not to proliferative markers in primary breast cancer. Int J Biol Markers (2000) 15:210–4.[Web of Science][Medline]
15 Reed W, Florems VA, Holm R, Hannisdal E, Nesland JM. Elevated level of p27, p21 and cyclin D1 correlate with positive oestrogen and progesterone receptor status in node-negative breast carcinoma patients. Virchows Arch (1999) 435:116–24.[CrossRef][Web of Science][Medline]
16 Takano Y, Takenaka H, Kato Y, Masuda M, Mikami T, Saegusa M, et al. Cyclin D1 overexpression in invasive breast cancers: correlation with cyclin-dependent kinase 4 and oestrogen receptor overexpression, and lack of correlation with mitotic activity. J Cancer Res Clin Oncol (1999) 125:505–12.[CrossRef][Web of Science][Medline]
17 Hui R, Ball JR, Macmillan RD, Kenny FS, Prall OW, Campbell DH, et al. EMS1 gene expression in primary breast cancer: relationship to cyclin D1 and oestrogen receptor expression and patient survival. Oncogene (1998) 17:1053–9.[CrossRef][Web of Science][Medline]
18 Zwijsen RM. CDK-independent activation of estrogen receptor by cyclin D1. Cell (1997) 88:405–15.[CrossRef][Web of Science][Medline]
19 Zwijsen RM. Ligand-independent recruitment of steroid receptor coactivators to estrogen receptor by cyclin D1. Genes Dev (1998) 12:3488–98.
20 Gaben AM, Saucier C, Bedin M, Redeuilh G, Mester J. Mitogenic activity of estrogens in human breast cancer cells does not rely on direct induction of mitogen-activated protein kinase/extracellularly regulated kinase or phosphatidylinositol 3-kinase. Mol Endocrinol (2004) 18:2700–13.
21 Sabbah M, Courilleau D, Mester J, Redeuilh G. Estrogen induction of the cyclin D1 promoter: involvement of a cAMP response-like element. Proc Natl Acad Sci USA (1999) 96:11217–22.
22 Hwang TS, Han HS, Hong YC, Lee HJ, Paik NS. Prognostic value of combined analysis of cyclin D1 and estrogen receptor status in breast cancer patients. Pathol Int (2003) 53:74–80.[CrossRef][Web of Science][Medline]
23 Zukerberg LR, Yang WI, Gadd M, et al. Cyclin D1 (PRAD1) protein expression in breast cancer: approximately one-third of infiltrating mammary carcinomas show overexpression of the cyclin D1 oncogene. Mod Pathol (1995) 8:560–7.[Web of Science][Medline]
24 Zhang SY, Caamano J, Cooper F, Guo X, Klein-Szanto AJ. Immunohistochemistry of cyclin D1 in human breast cancer. Am J Clin Pathol (1994) 102:695–8.[Web of Science][Medline]
25 Lidereau R, Callahan R, Dickson C, Peters G, Escot C, Ali IU. Amplification of the int-2 gene in primary human breast tumors. Oncogene Res (1988) 2:285–91.[Web of Science][Medline]
26 Fantl V, Richards MA, Smith R, et al. Gene amplification on chromosome band 11q13 and oestrogen receptor status in breast cancer. Eur J Cancer (1990) 26:423–9.[Web of Science][Medline]
27 Schuuring E, Verhoeven E, van Tinteren H, Peterse JL, Nunnink B, Thunnissen FB, et al. Amplification of genes within the chromosome 11q13 region is indicative of poor prognosis in patients with operable breast cancer. Cancer Res (1992) 52:5229–34.
28 Henry JA, Hennessy C, Levett DL, Lennard TW, Westley BR, May FE. Int-2 amplification in breast cancer: association with decreased survival and relationship to amplification of c-erbB-2 and c-myc. Int J Cancer (1993) 53:774–80.[Web of Science][Medline]
29 Michalides R, Hageman P, van Tinteren H, Houben L, Wientjens E, Klompmaker R, et al. A clinicopathological study on overexpression of cyclin D1 and of p53 in a series of 248 patients with operable breast cancer. Br J Cancer (1996) 73:728–34.[Web of Science][Medline]
30 van Diest PJ, Michalides RJ, Jannink L, van der Valk P, Peterse HL, de Jong JS, et al. Cyclin D1 expression in invasive breast cancer. Correlations and prognostic value. Am J Pathol (1997) 150:705–11.[Abstract]
31 Gillett C, Smith P, Gregory W, Richards M, Millis R, Peters G, et al. Cyclin D1 and prognosis in human breast cancer. Int J Cancer (1996) 69:92–9.[CrossRef][Web of Science][Medline]
32 Bilalovic N, Vranic S, Basic H, Tatarevic A, Selak I. Immunohistochemical evaluation of cyclin D1 in breast cancer. Croat Med J (2005) 46:382–8.[Web of Science][Medline]
33 Stendahl M, Kronblad A, Ryden L, Emdin S, Bengtsson NO, Landberg G. Cyclin D1 overexpression is a negative predictive factor for tamoxifen response in postmenopausal breast cancer patients. Br J Cancer (2004) 90:1942–8.[CrossRef][Web of Science][Medline]
34 Jirström K, Stendahl M, Rydén L, Kronblad Å, Bendahl P-O, Stål O, et al. Adverse effect of adjuvant tamoxifen in premenopausal breast cancer with cyclin D1 gene amplification. Cancer Res (2005) 65:8009–16.
35 Ahnström M, Nordenskjöld B, Rutqvist LE, Skoog L, Stål O. Role of cyclin D1 in erbB2-positive breast cancer and tamoxifen resistance. Breast Cancer Res Treat (2005) 91:145–51.[CrossRef][Web of Science][Medline]
36 Sherr CJ. The Pezcoller lecture: cancer cell cycles revisited. Cancer Res (2000) 60:3689–95.
37 Bilalovic NB, Vranic S, Basic H, Tatarevic A, Jselak I. Immunohistochemical evaluation of Cyclin D1 in breast cancer. Croat Med J (2005) 46:382–8.[Web of Science][Medline]
38 Zhou Q, Fukushima P, DeGraff W, et al. Radiation and the Apo2L/TRAIL apoptotic pathway preferentially inhibit the colonization of premalignant human breast cells overexpressing cyclin D1. Cancer Res (2000) 60:2611–15.
39 Pardo FS, Su M, Borek C. Cyclin D1 induced apoptosis maintains the integrity of the G1/S checkpoint following ionizing radiation irradiation. Somat Cell Mol Genet (1996) 22:135–44.[CrossRef][Web of Science][Medline]
40 Han EK, Begemann M, Sgambato A, Soh JW, Doki Y, Xing WQ, et al. Increased expression of cyclin D1 in a murine mammary epithelial cell line induces p27kip1, inhibits growth, and enhances apoptosis. Cell Growth Differ (1996) 7:699–710.[Abstract]
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