Relationship between epidermal growth factor and dehydroepiandrosterone and its sulphate in breast cyst fluid

Gross cystic breast disease is a common condition. Women with apocrine breast cysts may be at higher risk of breast cancer than women with cysts which are lined by flattened epithelium. Apocrine cysts have been shown to be associated with higher intracystic levels of dehydroepiandrosterone sulphate and intracystic sodium to potassium ratios of less than 3. In this study we measured the concentrations of epidermal growth factor, dehydroepiandrosterone and its sulphate in breast cyst fluid. The concentrations of all three analytes were significantly higher in cysts with intracystic Na+/K+ ratios of less than 3 than in cysts with electrolyte ratios of greater than or equal to 3 (P less than 0.001). The higher levels of EGF in cysts with low intracystic electrolyte ratios may provide an explanation of why women with apocrine cysts may be at greater risk of breast cancer. Positive correlations were obtained between concentrations of EGF and DHAS and between EGF and DHA, compatible with the view that intracystic EGF levels may be androgen-modulated. A positive correlation was also obtained between DHA and DHAS concentrations which supports the view that DHA in cyst fluid may be derived from the metabolism of DHAS in the breast cyst wall.     

Enterolactone in breast cyst fluid: correlation with EGF and breast cancer risk

The purpose of our study was to investigate whether enterolactone does accumulate into breast cyst fluid and whether it correlates with breast cancer risk. We included 258 women who had at least one cyst aspiration and known intracystic cation and epidermal growth factor (EGF) concentration values. For 191 of such women serum aliquots were also available. The median value of serum enterolactone was 17 nM/l (range 1–140 nM/l). The median intracystic level of enterolactone was much higher (63 nM/l, range 0–872 nM/l) and was significantly higher in type I cysts (p = 0.000). This cyst type contained also significantly higher levels of EGF (p = 0.000). A direct relationship was found between serum and cyst fluid enterolactone levels (p = 0.000) and between cyst enterolactone and EGF levels (p = 0.03), the latter correlation being evident especially in type II cysts. Twelve patients in the cohort of women were found to have developed a breast cancer. After univariate analysis breast cancer risk was associated with cyst type and especially with EGF concentration. No association was evident for enterolactone concentration. However, enterolactone concentration appeared to significantly decrease the risk of patients with high EGF concentrations. Our results show that enterolactone does accumulate in breast cysts, and that it modulates the risk related to the intracystic level of EGF, which is confirmed to be a strong predictor of breast cancer risk.     

Family history of breast cancer,age and benign breast disease

A major risk factor for breast cancer is having a first-degree family history of the disease. Benign breast disease (BBD), particularly atypical hyperplasia, is also associated with an increased risk of breast cancer. However, the relationship between family history of breast cancer and BBD is unclear. From 1989 through 1997, 80,995 participants in the Nurses' Health Study II were followed; 16,849 reported a first diagnosis of BBD. Pathology slides were reviewed for 1,465 women who reported having a tissue biopsy, and these were classified as nonproliferative BBD, proliferative BBD without atypia or atypical hyperplasia. Women with a family history of breast cancer were more likely to report a physician diagnosis of BBD [rate ratio (RR) = 1.38, 95% confidence interval (CI) 1.29-1.46]. The magnitude of this association declined with age from RR = 1.96 (95% CI 1.55-2.47) at 25-29 years to RR = 1.20 (95% CI 0.95-1.52) at age 45-50 years. Among women with proliferative disease, those with a family history of breast cancer were almost 3 times as likely to have atypia (prevalence odds ratio = 2.72, 95% CI 1.23-5.89) than those with no family history. In conclusion, women with a family history of breast cancer appear to be at increased risk of being diagnosed with BBD, in particular the high-risk types of BBD associated with a greatly increased risk of breast cancer. This link adds weight to the belief that BBD with atypia is a precursor or marker lesion for breast cancer.     

Intracystic epidermal growth factor level is predictive of breast-cancer risk in women with gross cystic disease of the breast

Women affected by gross cystic disease of the breast have an increased risk of breast cancer. We report here the incidence of breast cancer by cyst type and intracystic epidermal growth factor (EGF) concentration. Our retrospective study included 504 women who had at least 1 cyst aspiration between 1985 and 1993. Cyst fluids were processed for electrolyte concentration (n = 378), EGF concentration (n = 347) or both (n = 337). Age-standardized incidence ratios (SIRs) were estimated using the population of the Genoa Cancer Registry. A multivariate Poisson regression model was used to estimate relative risks (RRs) when the study groups were compared directly. By June 1999, 19 invasive breast cancers had developed in the cohort of women. The age SIR of breast cancer calculated for the whole cohort was 3.32 (95% confidence interval 2.00-5.18). The ratio was not affected by age and was only moderately increased in women with a positive family history of breast cancer and type I cysts (i.e., those with a Na+/K+ ratio <3). However, it was significantly increased in women with high EGF concentrations. Direct comparisons confirmed that age, cyst type and family history only moderately increased the RR, whereas EGF concentration was a strong predictor of risk. Our results confirm that women affected by palpable cysts have an increased risk of developing breast cancer and suggest that the risk is higher in women with high intracystic EGF concentrations.     

Mitogenic peptides in breast cyst fluid: relationship with intracystic electrolyte ratios

Women with palpable breast cysts which are lined with apocrine epithelium may be at higher risk of developing breast cancer than women with breast cysts which are lined with flattened epithelium, the former group being characterized by intracystic sodium to potassium ratios below 3, while the latter group has intracystic sodium to potassium ratios above 3. In this study the distribution of intracystic concentrations of the mitogenic peptides, epidermal growth factor, endothelin and gastrin-releasing peptide in the 2 groups of breast cysts were compared to see whether differences in concentrations between the 2 cyst groups might provide an explanation for the higher risk of breast cancer observed in women with "apocrine" breast cysts. The concentrations of epidermal growth factor and gastrin-releasing peptide were significantly higher in the low electrolyte ratio group (p less than 0.001). There was no difference in endothelin concentrations between the 2 groups. Negative correlations were found between epidermal growth factor concentrations and Na+/K+ and between gastrin-releasing peptide concentrations and Na+/K+ (p less than 0.001). A positive correlation was found between gastrin-releasing peptide and epidermal growth factor concentrations in breast cyst fluid (p less than 0.001). The significantly higher intracystic concentrations of both epidermal growth factor and gastrin-releasing peptide in the low-electrolyte-ratio group may provide an explanation for the higher risk of breast cancer which has been observed in women with "apocrine" breast cysts.     

Lipid-associated sialic acid levels in human breast cyst fluids

Summary Benign mammary gross cystic disease is the most common breast lesion. Women with apocrine changes of epithelium lining the cysts are at higher risk for developing breast cancer than the normal female population. Sialic acid has drawn considerable interest because of carbohydrate aberrations in malignant cells. The current investigation determined the concentrations of lipid-associated sialic acid (LASA) in 62 breast cyst fluids and sera. Data analyses show a significant increase in the mean values of LASA in metabolically active apocrine cysts when compared to the cysts with Na⁺/K⁺>3 (flattened cysts) (p<0.001). The greater LASA levels in cyst fluids with lower intracystic Na⁺/K⁺ ratios could represent an altered expression of biosynthetic activity of the surrounding apocrine cell surface sialoglycolipid metabolism, providing a possible explanation of why women with apocrine cysts may be at greater cancer risk and being useful in further studies on functional stage changes in the cysts and their relationship to breast cancer.     

Cathepsin D and epidermal growth factor in human breast cyst fluid

Cathespin D (Cath D) is a proteolytic enzyme secreted by human breast cancer cells with a growth promoting activity in vitro. In the present study, we measured Cath D and Epidermal Growth Factor/alpha Transforming Growth Factor (EGF/alpha-TGF) concentrations in the breast cyst fluid (BCF) of 43 patients with gross cystic disease of the breast. Both Cath D (median 2.45 pmoles mg-1 protein; range 0-4.84 vs 0.98 pmoles mg-1 protein; range 0-3.11) and EGF/alpha-TGF (28.71 ng mg-1 protein; range 7.05-50.63 vs 10.83 ng mg-1 protein; range 0.06-30.55) levels were higher in BCF of apocrine than flattened cysts (P less than 0.0005 and P less than 0.01, respectively). Premenopausal patients showed higher concentrations of Cath D (P less than 0.05) and EGF/alpha-TGF (P less than 0.05) than postmenopausal patients. A positive correlation was obtained between intracystic concentrations of Cath D and EGF/alpha-TGF (P less than 0.00001). The higher levels of Cath-D and EGF/alpha-TGF found in apocrine cysts could provide an explanation for the increased risk of subsequent breast cancer in women with this type of cyst.     

Effects of mammographic density and benign breast disease on breast cancer risk (United States)

Background: Having either a history of benign breast disease, particularly atypical hyperplasia or extensive mammographic breast density, is associated with increased breast cancer risk. Previous studies have described an association between benign breast disease histology and breast density. However, whether these features measure the same risk, or are independent risk factors, has not been addressed. Methods: This case–control study, nested within the prospective follow-up of the Breast Cancer Detection Demonstration Project, evaluated both benign histologic and mammographic density information from 347 women who later developed breast cancer and 410 age- and race-matched controls without breast cancer. Multivariate logistic regression analyses provided maximum-likelihood estimates of the odds ratios (OR) and 95% confidence intervals (CI) to evaluate the relative risk of breast cancer associated with each exposure. Results: Adjusting for mammographic density, the OR for atypical hyperplasia was 2.1 (95% CI: 1.3–3.6), and adjusting for benign breast histology, the OR for 75% density was 3.8 (95% CI: 2.0–7.2). Women with nonproliferative benign breast disease and 75% density had an OR of 5.8 (95% CI: 1.8–18.6), and women with <50% density and atypical hyperplasia had an OR of 4.1 (95% CI: 2.1–8.0). Conclusions: In this study, both benign breast disease histology and the percentage of the breast area with mammographic density were associated with breast cancer risk. However, women with both proliferative benign breast disease and 75% density were not at as high a risk of breast cancer due to the combination of effects (p = 0.002) as women with only one of these factors.     

Quantification of prostate-specific antigen immunoreactivity in human breast cyst fluids

Summary The frequency of gross cystic breast disease in premenopausal women and its possible association with in-creased breast cancer risk emphasises the importance of investigations relating to breast cyst fluid composition. In order to contribute to a better analysis of this medium, we have measured the presence of prostate-specific antigen immuno-reactivity in sixty-four human breast cyst fluids. Data analyses show that 35% of samples presented a level of this antigen < 0.05 µg/L, whereas 42 out of 64 cysts show a significant increase in the mean value of metabolically active apocrine cysts when compared to flattened cysts (p < 0.01). We report the first evidence that breast epithelium of gross cysts produces, secretes, and accumulates large amounts of prostate-specific antigen, a glycoprotein produced by prostatic tissue but recently detected in breast tumours, normal tissues, and during pregnancy. The production and intracystic accumulation of this serine protease in biosynthetically active apocrine type cyst can play a feasible role in the natural history of gross cystic breast disease as well as in the mechanism of cyst formation, enlargement, and transformation.     

Epidermal growth factor levels in human breast cyst fluid

Epidermal growth factor (EGF) seems to modulate the in vitro and in vivo growth of normal and neoplastic breast cells. We determined, by a radio-receptor assay, EGF levels in cyst fluid and in plasma of patients with gross cystic disease of the breast. The mean levels of EGF were lower in plasma than in breast cyst fluid (BCF) (p less than 0.001). In BCF of apocrine cysts we found higher EGF levels than in flattened cysts (p less than 0.001). The EGF content of apocrine BCF seems to be under sex steroid hormone control, being higher in reproductive age than in post menopause (p less than 0.05). Since it has been reported that patients with apocrine cysts are at a greater risk of developing breast cancer, we hypothesize that the high EGF concentration in apocrine BCF may play a role in the autocrine breast cyst epithelium growth control and neoplastic transformation.     

Oestradiol and epidermal growth factor in breast cyst fluid

Gross cystic breast disease may be categorised into 2 groups according to the intracystic cation ratios (Na+/K+ less than 3 and Na+/K+ greater than 3). It has been suggested that women in the low electrolyte ratio group may be at higher risk of developing breast cancer. Epidermal growth factor concentrations in breast cyst fluid were significantly higher in the low than in the high electrolyte ratio group but there was no significant difference in oestradiol concentrations between the two groups of breast cysts. A negative correlation was obtained between intracystic concentrations of epidermal growth factor and Na+/K+ (rs = -0.617, p less than 0.001). No evidence was found to support the hypothesis that concentrations of epidermal growth factor may be modulated by oestradiol. The higher concentrations of epidermal growth factor in the low electrolyte ratio group may provide an explanation for the higher risk of breast cancer observed in this group.     

Clonal chromosome-aberrations in fibrocystic breast disease-associated with increased risk of cancer

Short-term cultures of 29 samples of fibrocystic breast disease were cytogenetically analyzed. Clonal chromosome aberrations were found in six specimens, whereas the remaining 23 had a normal karyotype. Three of the abnormal samples displayed karyotypic anomalies previously associated with breast cancer, i.e., gain of Iq, trisomy 18 and cytogenetic multiclonality. Furthermore, all cytogenetically aberrant specimens had either proliferative disease without atypia or atypical hyperplasia, features of fibrocystic disease considered risk factors for subsequent breast cancer development. The cytogenetic similarities between breast carcinomas and proliferative fibrocystic breast disease add further support for classifying certain types of fibrocystic disease as a premalignant condition. Whether cytogenetically abnormal fibrocystic lesions are the ones that subsequently progress to cancer remains to be elucidated.     

Breast fluid cholesterol and cholesterol beta-epoxide concentrations in women with benign breast disease

Because cholesterol 5,6-epoxides have been reported to be mutagenic, carcinogenic, and cytotoxic, we investigated the relationship of these substances in breast fluid to histopathologically defined breast disease. We measured cholesterol and its oxidation product, 5 beta,6 beta-epoxide, in breast fluids from 68 women with biopsied benign breast disease (BBD) and 135 women with no history of breast disease (controls). Each biopsy was classified according to the most severe epithelial change: (a) nonproliferative epithelia; (b) hyperplasia without atypia; or (c) hyperplasia with atypia. Similar to our previous findings in control women, breast fluid cholesterol and beta-epoxide concentrations in women with BBD were associated with factors of interest in relation to breast cancer: concentrations increased with age and were higher in white than nonwhite women and in women who were past or current smokers; concentrations were lower in women who had given birth or breastfed within 2 yr. Increased breast fluid cholesterol and beta-epoxide concentrations were significantly associated with proliferative BBD (hyperplasia with or without atypia) compared to controls. After adjustment for covariates, the odds ratio for proliferative BBD associated with detectable versus nondetectable beta-epoxide concentrations was 8.5 (95% confidence intervals, 1.1, 68.8). Our findings suggest that the histological progression from normal epithelium to hyperplasia without atypia to atypical hyperplasia is associated with progressively increasing concentrations of both cholesterol and cholesterol beta-epoxide.     

Conjugated bile acids in breast cyst fluids: relationship to cation-related cyst subpopulations

Gross cystic breast disease is a benign lesion occurring in 7% of adult women. Apocrine changes of epithelium lining the breast cysts cause a higher risk of developing breast cancer. According to the possible role of bile acids in the pathogenesis of cancer, we analysed breast cyst fluids aspirated from 96 women for distribution of conjugated bile acid concentrations in the two subsets of breast cysts. Bile acid levels were correlated to K+ concentrations (P < 0.0001) and mean value was higher in Na/K < 3 metabolically active apocrine cyst as compared with Na/K > 3 flattened cyst (P < 0.001). Because bile acids could play an important role in the pathogenesis and growth of breast cancer, the significantly higher intracystic concentrations of these carcinogen compounds in apocrine Type I cysts might provide a further biological explanation as to why women with apocrine changes may be at higher breast cancer risk and could be useful for the biochemical knowledge occurring in the different functional stages of the gross breast cysts.     

Extra-tumoral breast tissue in breast-cancer patients: Variations with a family history of breast cancer

In order to study the relationship between benign breast changes, a family history of breast cancer and breast cancer, extratumoral breast tissue from 1259 breast-cancer patients in the WHO Collaborative Study of Neoplasia and Contraceptives was classified histologically. The occurrence of ductal hyperplasia, ductal atypia, sclerosing adenosis, adenosis, lobular atypia, lactational metaplasia, cysts, apocrine metaplasia, apocrine hyperplasia and atypia, duct ectasia and the epithelial-stromal ratio was evaluated as absent, mild, moderate or marked, along with registration of the quality and number of slides. Information on occurrence of cancer in the family was available for patients' mothers and grandmothers. Logistic-regression analyses showed that the prevalence odds ratios for lactational metaplasia, cysts, duct ectasia and calcification were significantly increased in patients with a family history of breast cancer. Apocrine metaplasia and hyperplasia were not significantly increased. The prevalence rates of ductal atypia (ductal carcinoma in situ and atypical ductal hyperplasia), ductal hyperplasia, sclerosing adenosis, adenosis and high epithelial-stromal ratio did not differ significantly among patients with or without a family history of breast cancer. A family history of other types of cancer did not influence the occurrence of any of the benign components. The findings in the present study are strikingly similar to those in our earlier comparison of extra-tumoral breast tissue in patients from countries with high and low risk of breast cancer. It is reasonable to conclude from this that a history of breast cancer in a woman's mother or grandmother and the factors leading to higher risk of breast cancer in some countries than in others have similar effects on the morphologic evolution of breast cancer through benign and pre-cancerous changes. Int. J. Cancer (Pred. Oncol.) 79:39–43, 1998.© 1998 Wiley-Liss, Inc.     

The influence of family history on breast cancer risk in women with biopsy-confirmed benign breast disease: results from the Nurses' Health Study

BACKGROUND: An association between histologic category of benign breast disease (BBD) and breast cancer risk has been well documented. However, the influence of a positive family history (FH) on breast cancer risk among women with biopsy-confirmed BBD is less certain. METHODS: The authors conducted a nested case-control study of BBD and breast cancer risk among 2005 women who were enrolled in the Nurses' Health Study. Cases were women with breast cancer who had a previous benign breast biopsy (n = 395 women). Controls were women who also had previous biopsy-confirmed BBD but were free from breast cancer at the time the corresponding case was diagnosed (n = 1610 women). BBD slides were reviewed and categorized as either nonproliferative lesions, proliferative lesions without atypia, or atypical hyperplasia (AH). RESULTS: Compared with women who had nonproliferative lesions and no FH, women who had proliferative lesions without atypia and a positive FH had a higher breast cancer risk (odds ratio [OR], 2.45; 95% confidence interval [95% CI], 1.61-3.70) than women with no FH (OR, 1.51; 95% CI, 1.12-2.06; P = .07). Among women who had AH, the OR for the development of breast cancer was 4.38 (95% CI, 2.93-6.55) for those with no FH and 5.37 (95% CI, 3.01-9.58) for those with a positive FH (P = .57). There was no significant interaction between the type of BBD and FH (P = .74). CONCLUSIONS: A positive FH of breast cancer slightly increased the breast cancer risk among women who had proliferative lesions without atypia. The increase in risk of breast cancer associated with FH was not significant among women who had AH.     

Biochemical study of cyst fluid in human breast cystic disease: a review

Summary Gross cystic disease of the breast may sometimes indicate an increased risk of breast cancer. Biochemical analysis of the cyst fluid could suggest which cysts are associated with breast cancer risk, as well as providing insights into the pathophysiology of this condition. The Na⁺/K⁺ ratio appears to be associated with the histological classification of the cyst. Sulfoconjugated estrogens and androgens, especially DHEA-S, are often found at high levels. A number of gross cystic disease fluid proteins (GCDFPs) have been described, and several polypeptide growth factors including EGF and IGF-I are frequently found. It is hoped that biochemical analysis of these components of breast cyst fluids will shed further light on the role of gross cysts in relation to breast cancer.     

Biopsy confirmed benign breast disease, postmenopausal use of exogenous female hormones, and breast carcinoma risk

BACKGROUND: A history of proliferative benign breast disease has been shown to increase the risk of developing breast carcinoma, but, to the authors' knowledge, how postmenopausal exogenous female hormone use, in general, has affected breast carcinoma risk among women with a history of proliferative breast disease with or without atypia has not been well established. METHODS: In the current case-control study, nested within the Nurses' Health Study, benign breast biopsy slides of 133 postmenopausal breast carcinoma cases and 610 controls with a history of benign breast disease, were reviewed. Reviewers had no knowledge of case status. RESULTS: Women with proliferative disease without atypia had a relative risk for postmenopausal breast carcinoma of 1.8 (95%, confidence interval [CI]: 1.1 to 2.8), and women with atypical hyperplasia had a relative risk of 3.6 (95%, CI: 2.0 to 6.4) compared with women who had nonproliferative benign histology. Neither current postmenopausal use of exogenous female hormones nor long term use for 5 or more years further increased the risk of breast carcinoma in the study population beyond that already associated with their benign histology. CONCLUSIONS: Women who had proliferative benign breast disease, with or without atypia, were at moderately to substantially increased risk of developing postmenopausal breast carcinoma compared with women who had nonproliferative benign conditions. In the current study, postmenopausal exogenous female hormone use in general did not further increase the breast carcinoma risk for women with proliferative benign breast disease. However, the analysis did not exclude the possibility of increased risk with a particular hormone combination or dosage.     

Benign breast disease and breast cancer: a case-control study in a cohort in Italy

Sixty-two cases of invasive breast cancer were identified in a large cohort of women previously treated for biopsy-proven benign breast disease (BBD) at the Breast Unit of CSPO, in Florence, along with a group of 315 controls, strictly matched by age and year of diagnosis. A pathologist reviewed and reclassified all the original BBD slides according to recently proposed criteria (no evidence of epithelial proliferation, epithelial proliferation without or with atypia). Information about potential confounding factors was collected during personal interviews. In comparison to the women with "non-proliferative" BBD, women classified as having "proliferative disease without atypia" showed a weak and non-significant increase in risk (OR 1.3; 95% CI: 0.5-3.5). In contrast, women with "atypical hyperplasia" were at very high risk of developing breast cancer (OR 13.0; 95% CI: 4.1-41.7). When planning mammography screening or other large-scale early-diagnosis programmes for breast cancer in the general female population, follow-up of high-risk subgroups of BBD patients should be considered.     

Sclerosing adenosis and risk of breast cancer

Over one million American women have a benign breast biopsy annually. Sclerosing adenosis (SA) is a common, but poorly understood benign breast lesion demonstrating increased numbers of distorted lobules accompanied by stromal fibrosis. Few studies of its association with breast cancer have been conducted, with contradictory results. We studied SA in the Mayo Benign Breast Disease (BBD) Cohort, which includes women who had benign biopsies at Mayo-Rochester 1967–2001. Breast cancer risk in defined subsets was assessed using standardized incidence ratios (SIRs), relative to the Iowa Surveillance, Epidemiology, and End Results registry. This BBD cohort of 13,434 women was followed for a median of 15.7 years. SA was present in 3,733 women (27.8 %) who demonstrated an SIR for breast cancer of 2.10 (95 % CI 1.91–2.30) versus an SIR of 1.52 (95 % CI 1.42–1.63) for the 9,701 women without SA. SA was present in 62.4 % of biopsies with proliferative disease without atypia and 55.1 % of biopsies with atypical hyperplasia. The presence of SA stratified risk in subsets of women defined by age, involution status, and family history. However, SA does not further stratify risk in women diagnosed with other forms of proliferative breast disease, either with or without atypia. SA is a common proliferative lesion of the breast which, as a single feature, conveys an approximate doubling of breast cancer risk. Its role in breast carcinogenesis remains undefined; its presence may aid in risk prediction for women after a breast biopsy.