Cyclin E and Survival in Patients with Breast Cancer
Khandan Keyomarsi, Ph.D., Susan L. Tucker, Ph.D., Thomas A. Buchholz, M.D., Matthew Callister, M.D., Ye Ding, Ph.D., Gabriel N. Hortobagyi, M.D., Isabelle Bedrosian, M.D., Christopher Knickerbocker, M.S., Wendy Toyofuku, B.S., Michael Lowe, B.S., Thaddeus W. Herliczek, M.D., and Sarah S. Bacus, Ph.D.
Background Cyclin E, a regulator of the cell cycle, affectsthe behavior of breast-cancer cells. We investigated whetherlevels of cyclin E in the tumor correlated with survival amongpatients with breast cancer.
Methods Tumor tissue from 395 patients with breast cancer wasassayed for cyclin E, cyclin D1, cyclin D3, and the HER-2/neuoncogene with the use of Western blot analysis. Full-length,low-molecular-weight, and total cyclin E were measured. Immunohistochemicalassessments of cyclin E were also made of 256 tumors. We soughtcorrelations between levels of these molecular markers and disease-specificand overall survival.
Results The median follow-up was 6.4 years. A high level ofthe low-molecular-weight isoforms of cyclin E, as detected byWestern blotting, correlated strongly with disease-specificsurvival whether axillary lymph nodes were negative or positivefor metastases (P<0.001). Among 114 patients with stage Ibreast cancer, none of the 102 patients with low levels of cyclinE in the tumor had died of breast cancer by five years afterdiagnosis, whereas all 12 patients with a high level of low-molecular-weightcyclin E had died of breast cancer within that period. In multivariateanalysis, a high total cyclin E level or high levels of thelow-molecular-weight forms of cyclin E were significantly correlatedwith poor outcome. The hazard ratio for death from breast cancerfor patients with high total cyclin E levels as compared withthose with low total cyclin E levels was 13.3 — abouteight times as high as the hazard ratios associated with otherindependent clinical and pathological risk factors.
Conclusions Levels of total cyclin E and low-molecular-weightcyclin E in tumor tissue, as measured by Western blot assay,correlate strongly with survival in patients with breast cancer.
The prognosis in patients with newly diagnosed breast canceris determined primarily by the presence or absence of metastasesin draining axillary lymph nodes.1 However, in approximatelyone third of women with breast cancer who have negative lymphnodes, the disease recurs, and about one third of patients withpositive lymph nodes are free of recurrence 10 years after local–regionaltherapy.2,3 These data highlight the need for more sensitiveand specific prognostic indicators.
A number of biologic factors have been used to refine risk categoriesin breast cancer. We have focused on the role of cyclin E indetermining the virulence and metastatic potential of tumorcells.4,5,6,7,8 In normal dividing cells, cyclin E regulatesthe transition from the G1 phase to the S phase9,10; a highlevel of the cyclin E protein accelerates the transition throughthe G1 phase.11,12
The cyclin E gene is amplified and the cyclin E protein is oftenconstitutively expressed in breast-cancer cell lines.6,8,13,14Some of these lines overexpress not only the full-length 50-kDcyclin E protein, but also up to five low-molecular-weight isoformsof cyclin E (ranging in size from 34 to 49 kD).6,7,15 Theseisoforms, which lack the amino terminus, are hyperactive, ascompared with the full-length protein, in phosphorylating substratesand inducing progression from the G1 phase to the S phase.16
Previous studies of the prognostic importance of cyclin E inbreast cancer have yielded contradictory results.17,18 In aretrospective analysis of 278 patients with breast cancer, Porteret al. found that overexpression of the full-length cyclin Eprotein and low levels of the cyclin-dependent kinase inhibitorp27 correlated with poor survival among patients with node-negativedisease.18 By contrast, in a study of 157 patients with breastcancer, Donnellan et al. reported that the correlation betweenhigh levels of cyclin E in the tumor cells and poor outcomelost its significance in a multivariate analysis.17 The antibodyto cyclin E used for immunohistochemical analysis in these studiescannot reliably detect the low-molecular-weight forms of cyclinE. Western blotting with an anti–cyclin E antibody targetedagainst the C-terminal domain of the protein, however, permitsdetection of both the full-length and low-molecular-weight isoformsof cyc-lin E.6,7,8,16
To determine whether levels of these isoforms are associatedwith outcomes in patients with breast cancer,7,19,20,21 cyclinE and its low-molecular-weight isoforms were measured by Westernblotting in samples of breast-cancer tissue from 395 patientsand by immunohistochemical techniques in samples from a subgroupof 256 patients. The levels were compared with established factorsthat predict disease-specific and overall survival. Total cyclinE levels and the level of low-molecular-weight forms of cyclinE as measured by Western blotting but not by immunohistochemicalanalysis proved to be strongly associated with survival amongpatients with breast cancer.
Methods
Tissue Samples and Study Patients
Tumor tissue was obtained from a centralized reference laboratory(Quantitative Diagnostic Laboratories). A total of 430 samplesconsisting of a minimum of 100 mg of breast-cancer tissue wereavailable. Each patient had received a diagnosis of breast cancerbetween 1990 and 1995 at 1 of 12 hospitals in the Chicago area.Specimens were shipped to the Wadsworth Center research laboratoriesfor Western blot analysis. This study was approved by the institutionalreview board of the Wadsworth Center.
The reference laboratory also provided base-line pathologicaland demographic data (obtained from the individual hospitals),as well as the steroid-receptor status, the DNA index, and theproliferation index (as described below). Information concerningclinical staging and survival was obtained from the tumor registriesof each hospital. Patients whose death was clearly documentedto be due to breast cancer were considered to have died of breastcancer; other deaths were considered not to have been causedby breast cancer. The data presented here are from 395 patientsfor whom data on outcome were available.
Hormone-Receptor, DNA, and Proliferation Assays
The procedures for the hormone-receptor and proliferation assayshave been described elsewhere.22,23,24 Specimens were scoredas positive for estrogen receptors or progesterone receptorsif they contained at least 11 fmol of specific binding sitesper milligram of protein.22 Specimens were considered to havea moderate-to-high proliferative index if 7 percent or moreof the nuclei were labeled with anti–Ki-67 antibody.24DNA ploidy values were determined by means of image cytometricmeasurements of nuclear DNA content.25,26
Western Blot Assays
Levels of full-length cyclin E, its low-molecular-weight isoforms,cyclin D1, cyclin D3, and the HER-2/neu oncogene were evaluatedby Western blot analysis of lysates prepared from specimensof frozen tumor tissue as previously described.7,27 The primaryantibodies used were as follows: monoclonal antibody HE12 tocyclin E,28 targeting the C-terminal epitope of the protein,diluted 1:10; polyclonal antibody to HER-2/neu (Oncogene Science),diluted 1:30; monoclonal antibodies to cyclin D1 and proliferating-cellnuclear antigen (Santa Cruz Biotechnology), diluted 1:250; monoclonalantibody to cyclin D3 (Transduction Laboratories), diluted 1:100;and actin monoclonal antibody (Boehringer–Mannheim) ata concentration of 0.63 µg per milliliter. Equivalentamounts of protein from two control cell lines (normal mammaryepithelial cells and breast-cancer cells) were included on eachgel as internal laboratory standards.
The protein levels in the Western blots were measured by densitometricscanning of the corresponding bands with the use of IPLab Gelsoftware (Scanalytics). On the basis of the densitometric values,the amounts of cyclin D1, full-length cyclin E, low-molecular-weightcyclin E, and total (full-length plus low-molecular-weight)cyclin E were scored as low (less than or equal to the levelof protein found in normal breast epithelium) or high (higherthan in the normal-cell controls). Specifically, cyclin E valueswere given a score of 0 to 3 (for full-length) and 0 to 10 (forlow-molecular-weight and total) on the basis of the densitometricvalues and were then distributed into two clusters — highand low, as compared with values obtained from normal tissues.For full-length cyclin E, expression was scored as high if thevalue was at least 0.5 (i.e., higher than the highest valuefor normal breast epithelium); a total of 14 normal tissue sampleswere examined. For both low-molecular-weight and total cyclinE, specimens with values of 1.2 or higher were classified ashigh. All normal-cell controls were negative for cyclin D3 andHER-2/neu. On Western blotting, densitometric values for theseproteins clustered into three groups and were scored as negative,low level, or high level. Densitometric values for actin wereused to standardize for equal protein loading among the samplesassayed. The Western blot analysis and scoring of the aforementionedbiologic markers were performed by investigators who were unawareof the patients' outcomes.
Immunohistochemical Studies
A subgroup of 256 samples of tumor tissue were available forimmunohistochemical analysis with the use of an affinity-purifiedpolyclonal antibody to cyclin E.5 We used the C-terminal peptidecorresponding to amino acids 381 to 411 of cyclin EL16 as anantigen in the affinity purification. This polyclonal antibodyis against the same epitope as monoclonal HE12 antibody andcan be used in Western blots to detect both the full-lengthand low-molecular-weight isoforms of cyclin E.5,7,8 Snap-frozentissues were embedded in Optimal Cutting Temperature compound,sectioned at 5-µm intervals, placed on coated slides,fixed, and stained for cyclin E as previously described.22,23,24At least two representative tissue sections from each patientwith breast cancer were examined. Each was scored from 0 to10 on the basis of the intensity of staining and the percentageof tumor cells stained. In 15 cases, sections of normal tissuewere tested along with tumor tissue. Scores for normal breast-cellcontrols ranged from 0 to 2. The tumor samples were then designatedas having either low cyclin E levels (less than or equal tothe level of protein found in normal breast epithelium, indicatedby a score of less than or equal to 2) or high cyclin E levels(higher than the level in normal-cell controls, indicated bya score of more than 2). Immunohistochemical analysis and scoringwere performed at Quantitative Diagnostic Laboratories by aninvestigator who was unaware of the results of Western blotanalysis and of patient outcome.
Statistical Analysis
Overall survival was calculated from the date of surgical excisionof the primary tumor to the date of death or last follow-up.For disease-specific survival, data for patients who died fromcauses other than breast cancer were censored at the time ofdeath. Overall survival and disease-specific survival curveswere computed by the Kaplan–Meier method.29 Error barsshown on the curves are 95 percent confidence intervals calculatedaccording to the method of Greenwood.30
Univariate analyses of disease-specific survival according tolevels of total and low-molecular-weight cyclin E and otherfactors (age, tumor size, nodal status, clinical stage, andvarious biologic markers) were performed with the use of a two-sidedlog-rank test.31 A multivariate analysis of disease-specificsurvival was performed with the use of the Cox proportional-hazardsmodel31 with both forward and backward stepwise inclusion offactors, with an inclusion criterion of P0.05 and an exclusioncriterion of P>0.05. Each model was fitted twice, once bya predominantly forward procedure in which the initial modelcontained only a constant term and once by a predominantly backwardprocedure in which all factors were included in the model atthe first step. For both procedures, addition and removal ofterms were considered at each step.
Results
Characteristics of the Patients
The median age of the study population was 64 years (range,29 to 95). The majority (92 percent) had stage I, II, or IIIbreast cancer. A total of 67 percent of the total study populationand 50 percent of patients with stage I disease had receivedadjuvant therapy. After a median follow-up of 6.4 years (range,1.5 to 11.0), 121 of the 395 patients (30.6 percent) had diedof breast cancer. The 5- and 10-year disease-specific survivalrates for the entire cohort of patients were 71 percent and62 percent, respectively. Overall survival was 66 percent at5 years and 47 percent at 10 years. The results of the univariateanalysis of disease-specific survival and overall survival accordingto clinical factors and biologic markers are shown in Table 1.As expected, there was a significant association betweenclinical stage and outcome.
Table 1. Results of Univariate Analysis of Prognostic Factors.
Biologic Markers
A representative Western blot analysis for cyclin E, cyclinD1, and proliferating-cell nuclear antigen in tissue samplesfrom 10 patients with breast cancer at various stages is shownin Figure 1A. The three patients with high levels of the low-molecular-weightforms of cyclin E (Patients 2, 6, and 10) died of breast cancer21, 16, and 14 months after diagnosis, respectively, whereasthe other seven patients, with undetectable or low levels oflow-molecular-weight forms of cyclin E, were alive at the timeof the last follow-up (57 to 75 months after diagnosis), withno evidence of disease. Figure 1B shows expression of cyclinE in 11 patients with early-stage breast cancer. Tissue fromPatients 2, 3, 6, 7, and 8 had a low level of cyclin E, andthese patients were free of disease at the time of last follow-up(99 to 108 months after diagnosis). Patient 1 died of unrelatedcauses and had no evidence of disease 23 months after diagnosis.Breast-cancer tissue from the remaining patients had high levelsof the low-molecular-weight forms of cyclin E, and these patientsdied from breast cancer between 33 and 65 months after diagnosis.Some tumors (those of Patient 2 in Figure 1A and Patient 5 inFigure 1B) had high levels of the low-molecular-weight formsof cyclin E but low levels of full-length cyclin E protein.In the entire cohort, there were 10 such patients, 9 of whomdied of breast cancer, with a median survival of 1 year (range,1 month to 6.9 years).
In Panel A, whole-cell lysates were extracted from 10 samples of infiltrating ductal carcinoma. Patient 1 had stage I disease and had no evidence of disease at last follow-up; Patient 2 had stage IIB disease and died; Patient 3 had stage IIA disease and had no evidence of disease at last follow-up; Patient 4 had stage IIA disease and had no evidence of disease at last follow-up; Patient 5 had stage I disease and had no evidence of disease at last follow-up; Patient 6 had stage IIIB disease and died; Patient 7 had stage I disease and had no evidence of disease at last follow-up; Patient 8 had stage IIA disease and had no evidence of disease at last follow-up; Patient 9 had stage IIB disease and had no evidence of disease at last follow-up; and Patient 10 had stage IIB disease and died. Each lane contained 50 µg of protein extract and was incubated with the indicated antibody. The control lanes represent a cultured normal mammary epithelial cell line (76N) and a cultured breast-cancer cell line (MDA-MB-157). PCNA denotes proliferating-cell nuclear antigen. In Panel B, whole-cell lysates were extracted from breast-cancer tissues from 11 patients with stage I or stage II breast cancer. Each lane contained 50 µg of protein extract and was incubated with the indicated antibody. Patient 1 died of other causes 23 months after diagnosis. Patients 2, 3, 6, 7, and 8 were alive without evidence of disease 99 to 108 months after diagnosis, whereas Patients 4, 5, 9, 10, and 11 died of breast cancer 33 to 65 months after diagnosis.
Univariate Analyses
The five-year overall survival and the five-year disease-specificsurvival were significantly longer among patients with low levelsof low-molecular-weight, full-length, or total cyclin E thanamong patients whose tumors had high levels of these proteins(P<0.001 by the log-rank test) (Table 1 and Figure 2). Figure 2Aand Figure 2D show disease-specific survival and overallsurvival, respectively, according to the level of total cyclinE in the tumor (low or high). The absence of cyclin D1 (Figure 2Band Figure 2E) and of cyclin D3 (Figure 2C and Figure 2F)was also associated with improved disease-specific and overallsurvival, but the correlations were less striking than thosefor cyclin E.
Figure 2. Kaplan–Meier Estimates of Disease-Specific Survival (Panels A, B, and C) and Overall Survival (Panels D, E, and F) for All 395 Patients.
Patients are grouped according to high or low total cyclin E levels (Panels A and D), and the presence or absence of cyclin D1 (Panels B and E) or cyclin D3 (Panels C and F), as determined by Western blot analysis. The numbers of patients at risk in each group are shown in Table 1. I bars represent the 95 percent confidence intervals.
Cyclin E and Stage of Disease
The proportion of tumors with high levels of cyclin E increasedwith increasing stage of disease (P<0.001 by the chi-squaretest; data not shown). Figure 3A shows disease-specific survivalaccording to clinical stage and total cyclin E level as determinedby Western blotting. In patients with stage I, II, or III breastcancer, a high total cyclin E level was strongly linked to disease-specificsurvival, but this was not the case among patients with stageIV disease (P=0.35) (Figure 3D). Of the 114 patients with stageI disease, 12 had a recurrence of breast cancer and died ofbreast cancer, with a median time to death of 4.1 years (range,1 to 7). All 12 — and only those 12 of the 114 patients— had a high level of cyclin E in their tumors (Figure 3A).In contrast, analysis of stage-specific survival accordingto the cyclin E level measured by immunohistochemical analysisshowed a significant association only among patients with stageIII disease (data not shown).
Figure 3. Kaplan–Meier Estimates of Disease-Specific Survival According to Total Cyclin E Expression, as Measured by Western Blot Analysis.
The numbers of patients at risk in each group are shown in Table 1. I bars represent the 95 percent confidence intervals.
Proportional-Hazards Modeling
We performed proportional-hazards modeling of disease-specificsurvival and overall survival according to Western blottingand immunohistochemical measures of cyclin E. When they wereincluded individually in separate models, all measures weresignificantly associated with disease-specific survival andoverall survival. High levels of total cyclin E and high levelsof low-molecular-weight cyclin E were associated with hazardratios for death from breast cancer of 33.0 and 20.8, respectively,whereas the hazard ratio for death from breast cancer amongpatients with high levels of cyclin E as measured by immunohistochemicalanalysis was 2.90. When all four of these measures of cyclinE were included simultaneously in a proportional-hazards modelfitted to the data from the 256 patients with immunohistochemicaldata, only the associations with the total cyclin E level andthe low-molecular-weight cyclin E level as measured by Westernblot analysis retained statistical significance. The associationswith the levels of total cyclin E and low-molecular-weight cyclinE, but not the association with the level of full-length cyclinE, retained significance when a model containing these factorswas fitted to the data from all 395 patients.
Immunohistochemical Analysis versus Western Blot Analysis
We next compared immunohistochemical analysis with Western blottingfor measurement of cyclin E. Figure 4A and Figure 4D show disease-specificsurvival and overall survival, respectively, for patients withlow or high values of cyclin E as measured by immunohistochemicalanalysis. In Figure 4B and Figure 4E, disease-specific survivaland overall survival, respectively, are plotted for patientswith high or low levels of cyclin E as measured by Western blottingin the subgroup of patients who had low levels of cyclin E asmeasured by immunohistochemical analysis. Among 120 patientswith low cyclin E levels as scored by immunohistochemical analysis,we identified 21 with elevated levels of cyclin E on Westernblot assays. The five-year disease-specific survival rate amongthese patients was 19 percent (95 percent confidence interval,5 to 39). Conversely, of 136 patients with high scores for cyclinE as judged by immunohistochemical analysis, 74 had low cyclinE levels as measured by Western blot assay. These 74 patientshad a five-year disease-specific survival rate of 91 percent(95 percent confidence interval, 82 to 96) (Figure 4C and Figure 4F).
Figure 4. Kaplan–Meier Estimates of Disease-Specific Survival and Overall Survival among Patients with Immunohistochemical Data on Cyclin E.
Survival among all 256 patients with data is shown in Panels A and D. The same patients are also grouped according to cyclin E levels (high or low), as measured by Western blotting. Panel B shows estimates of disease-specific survival and Panel E estimates of overall survival as a function of total cyclin E levels as determined by Western blot analysis in the subgroup of patients with low cyclin E levels as measured by immunohistochemical analysis. Panel C shows estimates of disease-specific survival and Panel F estimates of overall survival as a function of total cyclin E levels as determined by Western blot analysis in the subgroup of patients with high cyclin E levels as measured by immunohistochemical analysis. The numbers of patients at risk in each group are shown in Table 1. I bars represent the 95 percent confidence intervals.
Multivariate Analysis
The results of the multivariate analysis of factors predictiveof disease-specific survival and overall survival are presentedin Table 2. For these analyses, all factors shown in Table 1were initially included in the model as potential risk factors.Factors for which there were missing data (e.g., cyclin E levelas measured by immunohistochemical analysis and ploidy) andthat were not selected by the stepwise procedure were subsequentlyomitted, and the stepwise procedure was repeated in order toobtain the final model. The forward and backward stepwise proceduresboth led to the same final model, shown in Table 2. A high totalcyclin E level was strongly associated with poor outcome, witha hazard ratio for death from breast cancer of 13.3. For highlevels of the low-molecular-weight isoforms of cyclin E, thehazard ratio for death from breast cancer was 2.1. Althoughpositive lymph nodes, negative estrogen-receptor status, andlate-stage disease remained significant predictors of deathfrom breast cancer, the association with a high cyclin E levelwas substantially stronger. Associations of death from breastcancer with cyclin E scores according to immunohistochemicalanalysis and with levels of cyc-lin D1, cyclin D3, and HER-2/neudid not reach statistical significance in the multivariate analysis.
Table 2. Independent Factors Predictive of Death from Breast Cancer and Death from Any Cause.
Discussion
In this retrospective study, we examined the correlation betweenlevels of cyclin E and its low-molecular-weight forms in breast-cancertissue and survival in patients with breast cancer. We foundthat the hazard ratio for death due to breast cancer in patientswith high levels of total cyclin E in the tumor was higher thanthe hazard ratios associated with any other biologic markerwe examined; it was more than seven times as high as the hazardratio associated with lymph-node metastases. We also found thatestrogen- and progesterone-receptor status and levels of HER-2/neu,cyclin D1, and cyclin D3 significantly correlated with disease-specificsurvival, but in a multivariate analysis, the cyclin E levelwas most closely associated with outcome. All patients withstage I disease and a high cyclin E level as determined by Westernblot analysis died of breast cancer.
Previous investigations of the prognostic value of cyclin Elevels in breast-cancer tissue have produced conflicting data.These studies used immunohistochemical techniques,17,18 buttumor cells often overexpress low-molecular-weight forms ofcyclin E7 that lack the amino terminal targeted by the antibodiesused in most immunohistochemical assays. In our immunohistochemicalanalysis of cyclin E, we used an antibody against the C terminalof the protein that recognizes both the full-length and thelow-molecular-weight forms of cyclin E that are detectable byWestern blot analysis.5 However, we found discordance in 37percent of the samples between the results of immunohistochemicalanalysis and those of Western blot assays, even though the twoantibodies used in these assays targeted the same epitope ofcyclin E. Since both antibodies target the same region of theprotein, the reason for the difference in the ability of immunohistochemicalanalysis and Western blotting to assess cyclin E status reliablyis not entirely clear.
The prognostic significance of cyclin E may be the result ofsome of its biologic functions. The low-molecular-weight formsof cyclin E are constitutively expressed in breast cancer andfacilitate the transition from the G1 phase to the S phase moreeffectively than the full-length form of the protein.8,16 Constitutiveoverexpression of cyclin E (but not cyclin D1 or cyclin A) inimmortalized rat-embryo fibroblasts and human breast epithelialcells has been shown to cause chromosomal instability.32 Inabout 10 percent of transgenic mice that express human cyclinE, mammary carcinoma develops, demonstrating that cyclin E hasoncogenic potential.33 Finally, elastase, which mediates cleavageof cyclin E into its low-molecular-weight isoforms,16 has alsobeen implicated in tumor invasion and development of the metastaticphenotype.34 This spectrum of biologic activity suggests thatcyclin E may have multiple roles in the development and outcomeof breast cancer.
In summary, in this retrospective analysis, we found high levelsof low-molecular-weight and total cyclin E, as measured by Westernblotting, to be sensitive and specific prognostic indicatorsin patients with breast cancer. Our results are encouraging,but they must be validated in a prospective trial before theycan be applied clinically. The development of molecular stagingof breast cancer may have important implications for treatment,particularly in patients with early-stage disease, many of whomcurrently receive toxic systemic treatment with little benefit.
Supported by a grant (DAMD-17-94-J-4081, to Dr. Keyomarsi) fromthe U.S. Army Medical Research and Materiel Command; and grants(R29-CA666062 and R01-CA87548, to Dr. Keyomarsi, and CA16672and T32CA77050) from the National Cancer Institute. Dr. Buchholzis supported by a Career Development Award (BC980154) from theBreast Cancer Research Program of the U.S. Army Medical Researchand Materiel Command.
Dr. Keyomarsi holds U.S. patents 5,543,291 (method of detectingcarcinoma) and 5,763,219 (cyclin E variants and use thereof).Dr. Hortobagyi reports receiving research support from RibozymePharmaceuticals.
We are indebted to the Wadsworth Center at the New York StateDepartment of Health for support and resources; to Dr. CharlesE. Lawrence for his advice during the course of this study;to Dot Chin, Pat Fox, and Christopher Danes for technical assistance;to the 12 hospitals (Hinsdale Hospital, LaGrange Memorial Hospital,Swedish Covenant Hospital, Glen Oaks Medical Center, HumanaHospital, Hoffman Estates Hospital, Elmhurst Hospital, EdwardHospital, Eisenhower Medical Center, Gottlieb Hospital, Boyceand Bynum Hospital, and St. Mary's Health Center) and theirtumor-registry departments for providing frozen tissue and respondingto follow-up questionnaires; and to Dr. James Cox for his criticalreading of the manuscript. This work is dedicated to the memoryof Taranoam Amir-Ebrahimi Zamani.
Source Information
From the Department of Experimental Radiation Oncology (K.K.), the Breast Cancer Research Program (K.K., T.A.B., M.C., G.N.H.), the Department of Biomathematics (S.L.T.), the Division of Radiation Oncology (T.A.B., M.C.), the Department of Breast Medical Oncology (G.N.H.), and the Department of Surgical Oncology (I.B.), University of Texas M.D. Anderson Cancer Center, Houston; the Division of Molecular Medicine, Wadsworth Center, Albany, N.Y. (Y.D., C.K., W.T., M.L., T.W.H.); and Quantitative Diagnostic Laboratories, Elmhurst, Ill. (S.S.B.).
Address reprint requests to Dr. Keyomarsi at the Department of Experimental Radiation Oncology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 66, Houston, TX 77030-4095, or at kkeyomar{at}mdanderson.org.
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Cyclin E in Breast Cancer
Kang Y., D'Hondt L., André M., Canon J.-L., Yee D., Rabinowitz I., Bedrosian I., Tucker S. L., Keyomarsi K.
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N Engl J Med 2003;
348:1063-1064, Mar 13, 2003.
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A correction has been published: N Engl J Med 2003;348(2):186.
0.05 and an exclusion criterion of P>0.05. Each model was fitted twice, once by a predominantly forward procedure in which the initial model contained only a constant term and once by a predominantly backward procedure in which all factors were included in the model at the first step. For both procedures, addition and removal of terms were considered at each step. 
depend on cell context and p27Kip1 expression. Cell Growth Differ 1997;8:393-405. [Abstract]
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