Affiliations of authors: H. Gobbi, Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN, and Department of Anatomic Pathology, School of Medicine, Federal University of Minas Gerais, Brazil; W. D. Dupont, W. D. Plummer, Jr., P. A. Schuyler (Department of Preventive Medicine), J. F. Simpson, S. J. Olson (Department of Pathology), C. L. Arteaga (Departments of Medicine and Cell Biology), D. L. Page (Departments of Pathology and Preventive Medicine), Vanderbilt University School of Medicine, Nashville, TN.
Correspondence to: William D. Dupont, Ph.D., Department of Preventive Medicine, Vanderbilt University School of Medicine, A-1124 Medical Center North, Nashville, TN 37232-2637 (e-mail: bill.dupont{at}vanderbilt.edu).
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ABSTRACT |
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INTRODUCTION |
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Proliferative disease without atypia consists of a group of histologically defined lesions that are associated with a mild elevation in breast cancer risk (1,7). The most common of these lesions is moderate or florid hyperplasia of the usual type (1,7). This study focuses on the differences in TGF-ß-RII expression among these latter lesions, which are referred to as epithelial hyperplasia lacking atypia (EHLA).
TGF-ßs mediate their activity by high-affinity binding to a hetero-oligomeric complex composed of type I and type II receptors (8). Loss of response to growth inhibitory action of TGF-ß is a common phenomenon in tumor progression. Previous studies (5,9-13) have shown that, in tumor systems, TGF-ß responsiveness is positively associated with TGF-ß-RII levels. We studied levels of TGF-ß-RII in EHLA and risk of subsequent invasive breast carcinoma.
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SUBJECTS AND METHODS |
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We conducted a nested case-control study of women from the Nashville Breast Study Cohort. This cohort consists of women who underwent biopsy revealing benign breast tissue at three Nashville hospitals: Vanderbilt University Medical Center between 1952 and 1985, St. Thomas Hospital between 1952 and 1981, or Baptist Hospital between 1952 and 1968. Details on this cohort have been published elsewhere (1,14,15). In brief, a patient's entry biopsy was her first biopsy that revealed benign breast parenchyma at a study hospital during the recruitment period. Patients were eligible for follow-up if, at the time of their entry biopsy, they were residents of Tennessee or Kentucky and did not have breast cancer diagnosed before or within 6 months of their entry biopsy. Patients were excluded if their entry biopsy slides or charts were lost. Follow-up was begun 6 months after the entry biopsy was performed. In this report, "follow-up" always refers to follow-up in the Nashville Breast Study Cohort.
This study was approved by the Institutional Review Board of Vanderbilt University Medical School. We obtained informed consent for participation and follow-up in the study from 9701 study subjects or their next of kin. This number represents 87% of those women eligible for follow-up. Follow-up was terminated when the first of the following events occurred: The subject had her exit interview (7620 women), she developed invasive breast cancer (443 women), she died of causes other than breast cancer (1028 women), she lost both of her breasts for reasons other than invasive breast cancer (372 women), or she was known not to have developed breast cancer but was lost to subsequent follow-up (238 women).
Selection of Case Patients and Control Patients
We considered members of the Nashville Breast Study Cohort for selection as case patients or control patients for this study if they underwent a breast biopsy containing proliferative disease without atypia between 1965 and 1978. Their first biopsy in this time interval was their diagnostic biopsy. To be eligible for selection they must not have had a diagnosis of breast cancer or atypical hyperplasia before their diagnostic biopsy. Subjects were excluded if the paraffin-embedded tissue blocks from their diagnostic biopsy were missing. Case patients consisted of all 71 eligible subjects whose diagnostic biopsy occurred between 1965 and 1978 and who subsequently developed invasive breast cancer. Two control patients were selected for each case patient matched on age at biopsy and year of biopsy. To be selected as a control patient for a specific case, a patient had to be in the risk set for that case patient at the time when the case patient developed breast cancer (16). That is, she had to have follow-up after her diagnostic biopsy that was at least as long as that for the specific case and must not have developed breast cancer by that time. She could develop breast cancer at a later date, which, in fact, did happen for four of the selected control patients. We did not match any control patients to more than one case patient (selection without replacement). These selection rules produced a nested case-control study consisting of 71 case patients who subsequently developed breast cancer, 138 distinct control patients who did not develop breast cancer at anytime during follow-up, and four control patients who developed breast cancer (and therefore were also case patients) after they were selected as control patients, as described above. There were 17 patients in the case patient group and 23 in the control patient group who did not have EHLA in their diagnostic biopsy. Thus, analyses that are restricted to women with EHLA involved 54 case patients and 115 control patients. The choice of the biopsy interval for this study was affected by the need for long-term follow-up on the one hand and concern about the age of biopsy tissue on the other. The 1965-1978 interval was a compromise that was influenced by these two issues. During the course of this study, however, we did not observe any evidence that immunohistochemistry was compromised by the age of the tissue samples.
Tissue Samples
We cut sequential 5-µm sections from formalin-fixed, paraffin-embedded tissue specimens of the diagnostic biopsies of 209 case patients and control subjects. One section from each specimen was stained with hematoxylin-eosin to verify the presence of epithelial hyperplasia. One sequential section was used for TGF-ß-RII immunohistochemistry.
Histologic Definitions and Analyses
The definitions that we use to classify benign breast disease have been described elsewhere (1,7). Proliferative disease connotes either atypical hyperplasia or proliferative disease without atypia (7). Proliferative disease without atypia refers to a group of lesions that are associated with a mild elevation in breast cancer risk (1-3,17). One of the most prevalent of these lesions is EHLA, which has also been described as moderate or florid hyperplasia of usual type (1,7). Complex fibroadenomas contain either cysts, sclerosing adenosis, epithelial calcifications, or papillary apocrine change (15). We made these diagnoses on the entry biopsies of the entire cohort. The hematoxylin-eosin-stained slides of the diagnostic biopsies of case patients and control patients were assessed for the different components of proliferative disease without atypia, including EHLA without knowledge of the subsequent breast cancer outcome.
Immunohistochemical Evaluation
We performed immunostaining on a Ventana ES-automated immunostainer (Ventana, Tucson, AZ) by use of an affinity-purified rabbit polyclonal antibody (C-16; Santa Cruz Biotechnology, Santa Cruz, CA) raised against human TGF-ß-RII. This antibody recognizes sequences corresponding to amino acids 550-565 located at the C-terminal region of the TGF-ß-RII protein. To confirm antibody specificity, we incubated the TGF-ß-RII antibody with a 10-fold excess of the TGF-ß-RII synthetic peptide available from the manufacturer. Control sections were then stained, and no immunostaining was detected. Other investigators (18-20) have obtained similar results demonstrating the specificity of this antibody.
A pretest was done to establish the best staining conditions. Three antibody dilutions (1, 2, and 4 µg/mL) were tested by use of three conditions: no pretreatment, heat-induced epitope retrieval, and enzyme pretreatment. A concentration of 2 µg/mL by use of Protease I (Ventana) pretreatment gave the best results, and this method was applied to all specimens. We used normal breast tissue obtained from reduction mammoplasty specimens as positive controls for the TGF-ß-RII antibody. In these specimens, all of the epithelial cells stained with the TGF-ß-RII antibody. Epithelia of normal ducts and lobular units adjacent to the EHLA lesions were used as internal controls.
We used a semiquantitative approach to distinguish levels of expression among TGF-ß-RII-positive specimens. We considered the staining to be positive when the cytoplasm of epithelium of normal ducts or lobular units stained for TGF-ß-RII. We (D. L. Page and H. Gobbi) conducted an initial review of all immunostained slides to choose cut points and a scoring system that permits reproducibility of this semiquantitative analysis. After an extensive joint review of individual lesions at a double-headed microscope, we chose cut points for the reported system that fostered easy agreement from the available slides. When there was discordance (<5% of the case patients), a consensus classification was attained by joint review. The better developed (larger) EHLA lesions were preferentially evaluated and were usually concordant with the few other lesions available for study in each patient. Also, in evaluating lobular units, we preferentially chose larger units as well as units closer to the evaluated lesion. There was usually little variability between the two or three such available units. The percentage of positive cells in hyperplastic lesions was assessed as less than 25%, 25%-75%, and greater than 75%. We classified the pattern as homogeneous if more than 95% of positively stained cells had a similar staining intensity; otherwise, it was classified as heterogeneous. The intensity of positive staining was grouped into weak, moderate, and strong categories by making a comparison with positive epithelial cells of normal ducts and lobular units within the same biopsy specimen.
Statistical Analysis
We used the Kaplan-Meier method (21) to draw the cumulative
morbidity curves in Fig. 1. Follow-up in this figure was censored after 30
years because of the small number of women with longer follow-up times. We estimated the risk
of invasive breast cancer in patients with EHLA relative to women with neither proliferative
disease nor complex fibroadenoma. This risk is given both for women in their first 12 years after
EHLA diagnosis and for women in subsequent years. We estimated these risks by
time-dependent hazard regression analysis (21). The covariates in this
analysis were indicator step functions that denoted a diagnosis of EHLA and a time since
diagnosis that was either less than or equal to 12 years or greater than 12 years, respectively.
These risks were adjusted for age at diagnosis by including this age as a covariate in the model.
We chose the 12-year cut point by maximizing the model deviance compared with models that
used other cut points (22). The adequacy of our final model was assessed
by comparison with more complex time-dependent covariate models. There is compelling
evidence that the relative hazard of breast cancer morbidity associated with proliferative breast
disease decreases with increasing time since the patient's diagnostic biopsy (14). It is for this reason that we used a time-dependent covariate model when
estimating relative hazard for such lesions. The advantage of using indicator step functions as
covariates is that it permits the derivation of relative risks associated with different time intervals
following biopsy. Although the true relative hazard is undoubtedly a continuous function of time,
our model fitting indicated that a step function with a single step at 12 years provided a good fit
to the data and that there was little to be gained by adding additional steps to the model.
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Breast cancer standard morbidity ratios (28) for women with different histologic diagnoses were adjusted for age at biopsy and year of biopsy in comparison to women from the Connecticut Tumor Registry (29). (These ratios equal the observed number of breast cancers divided by the expected number of breast cancers given the follow-up experience of the cohort.) All P values in this report are derived with respect to two-sided alternative hypotheses.
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RESULTS |
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In the nested case-control study, the expression of TGF-ß-RII was detectable in the
epithelial cells of normal breast ducts and lobular units, exhibiting a cytoplasmic distribution
(Fig. 2, A). The myoepithelial cells of terminal and large ducts stained
homogeneously for TGF-ß-RII; however, in the lobular units, these cells were rarely positive
(Fig. 2,A). The cytoplasm of stromal cells and of endothelial cells,
known TGF-ß targets, also stained for TGF-ß-RII (Fig. 2,A).
There was a variation in the staining pattern and staining intensity for TGF-ß-RII expression
in epithelial cells of hyperplastic lesions among the specimens (Fig. 2,B-D). Some of the cells were often negative alongside cells that were lightly or strongly
positive. Fig. 2
indicates the range of positivity for individual cells. More
than 75% of the
epithelial cells of normal lobular units were positive for TGF-ß-RII in 136 of 138 control
patients and in 69 of 71 case patients. The intensity of staining of normal lobular units was
similar between case patients and control patients.
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The relationship between TGF-ß-RII expression within EHLA
lesions and breast cancer risk is summarized in.Table
1. This table shows the effects of extent of
expression, pattern of expression, and intensity of expression on
breast cancer risk. Breast cancer risk increased as the proportion of
cells expressing TGF-ß receptors decreased (test for trend
P = .008). Women with less than 25% TGF-ß-RII-positive
cells in their EHLA lesions had 3.41 times the risk of subsequent
invasive breast cancer than did women with histologically identical
lesions but with more than 75% positive cells (P = .02).
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The combined effects on breast cancer risk of TGF-ß-RII
expression in normal lobular units and epithelial hyperplasia lacking
atypia are shown in Table 2. The results suggest an
interaction between loss of TGF-ß-RII expression in EHLA lesions
and a heterogeneous pattern of TGF-ß-RII expression in adjacent
lobular units with normal morphology. Among women with normal breast
lobular units having a heterogeneous staining pattern and EHLA, the
odds ratios for breast cancer were 0.742 (95% CI = 0.3-1.8), 2.85
(95% CI = 1.1-7.1), or 3.55 (95% CI = 1.0-10.0) in women whose
EHLA
had greater than 75%, 25%-75% and less than 25%
TGF-ß-RII-positive epithelial cells, respectively (test for trend
P = .003). Among all study subjects, regardless of whether
they had EHLA or how TGF-ß-RII was expressed in their EHLA, women
who showed a heterogeneous pattern of TGF-ß-RII expression in their normal
lobular units had 1.66 times the breast cancer risk of patients whose normal
lobular units had a homogeneous pattern of expression (95% CI = 0.91-3.0).
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DISCUSSION |
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To date, the most well-established breast cancer risk factors associated with benign breast lesions are histologic. Moderate or mild elevations of breast cancer risk are associated with proliferative disease with or without atypia, respectively (1-3,17,40). In this study, the TGF-ß-RII findings are restricted to women who have proliferative disease lacking atypia. Thus, by examining TGF-ß-RII expression, we are able to identify a threefold difference in breast cancer risk among comparable women with histologically identical lesions.
Our knowledge of TGF-ß biology enhances the plausibility of the epidemiologic findings of this report. TGF-ß is a potent cell regulatory polypeptide that affects cell growth, differentiation, matrix production, and immune function (41) and acts as a negative autocrine growth inhibitor (4,41). Malignant progression is associated with the loss of sensitivity to growth inhibition by TGF-ß (5,6,42,43). Loss of TGF-ß response has been shown to be temporally associated with tumor development and progression in cultured breast (13,44), colon (12,42), and other malignant (9,45,46) cell lines. Transgenic mice that overexpress TGF-ß1 are resistant to induced mammary tumor formation (47). Loss of expression of TGF-ß-RII has been demonstrated in human cancers (10,48,49), and loss of receptors or the ability to activate secreted latent TGF-ß may be critical events in breast tumorigenesis (4,6,11,50).
In this study, we found variable expression of TGF-ß-RII in EHLA by use of a semiquantitative grading scheme. Although interpretation of these data is subject to the quantitative limitations of immunohistochemical methods, our double-blind evaluation protects our findings from diagnostic bias. Our results demonstrate that TGF-ß-RII is expressed by normal epithelium of ducts and lobular units and in mammary EHLA. Women with EHLA with reduced TGF-ß-RII expression have an elevated risk of subsequent invasive breast cancer. Thus, reduction in TGF-ß-RII expression appears to be an early event in the progression from hyperplasia to malignancy. This does not necessarily imply that EHLA with reduced TGF-ß-RII expression is a deterministic precursor of breast cancer.
Breast cancer is the second largest cause of cancer mortality among North American women today; it has the highest incidence of potentially lethal cancers and is certainly the most feared. It is thus of great importance to be able to reassure women who are at low risk of breast cancer and to initiate preventive measures in women who are at high risk of this disease. Unfortunately, most of the known risk factors for sporadic breast cancer are associated with modest levels of elevated cancer risk. In this report, we present evidence that differences in expression of the TGF-ß-RII in ordinary hyperplastic breast lesions affect subsequent breast cancer risk. These results in combination with known histologic and epidemiologic breast cancer risk factors should help to refine the clinical management of proliferative breast disease.
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NOTES |
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We thank Marcia G. Freudenthal, Cheryl D. Sharpe, Julia F. Smith, and Kay B. Covington for their skilled and dedicated pursuit of follow-up information; Drs. Steven J. Schultenover, Barrett Brantley, Richard R. Oldham, and more than 60 Nashville surgeons and the staffs of the tumor registries and record departments of the three Nashville hospitals for their cooperation and aid in patient follow-up; the thousands of women who have participated in our studies; and Drs. Marie R. Griffin and Harold L. Moses for their helpful suggestions.
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Manuscript received April 21, 1999; revised October 4, 1999; accepted October 7, 1999.
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