In our study, patients with BRCA1
gene mutations were tested for the expression of steroid receptors (ERβ, ERα and PgR) and the HER-2 receptor in breast cancer tissue. In this group, ERβ was more common (42%), while ERα and PgR occurred less frequently (14.5% and 12.5% respectively). In the control group, the expression of ERα and PgR was 57.5 and 64%, respectively. In the case of ERα and PgR, the differences between the two groups were found to be statistically significant (p = 0.001). Those values are similar to those described by other authors [8
]. In the case of ERβ, however, the differences of expression between those two groups were small.
Most of our control group patients were tested for the presence of BRCA1 mutations. Although those tests were not performed on all the controls, this cannot influence the overall findings of the study since in Poland BRCA1 mutations (unselected for age) occur only in about 3% of all breast cancer patients [23
It has been pointed out in many studies that BRCA1
positive breast cancers rarely express ERα [8
]. Further confirmation of that observation comes from recent studies made with the use of the cDNA microarray technique, showing that breast cancers may vary considerably in their molecular profile [24
]. The largest group consists of tumors with a cellular profile matching that of the inner layers of the mammary glands, such as luminal cells (luminal types) and another group consists of tumors with basal cell profiles (basal types). These two groups differ in their expression of ERα. The luminal types express ERα, while the basal types usually do not. cDNA studies of breast cancers with underlying BRCA1
gene mutations show that the most common cancer type in this group is basal [26
]. Moreover, basal type tumors show expression of receptors for epidermal growth factor (EGFR) more often. Generally, about half of the patients with BRCA1
gene mutations present the phenotype ER(-)/HER2(-)/EGFR(+) of the basal type of tumor, which is usually associated with poor prognosis [26
]. On the other hand, there are data that suggest that the prognosis for BRCA1
-positive patients is no worse than that for patients without mutations [10
]. This discrepancy may suggest the influence of some incompletely explored prognostic and predictive factor(s).
Recent analyses suggest that ERβ may be an independent prognostic and predictive factor in the course of breast cancer [29
]. However, its role has not yet been fully discovered. It is noteworthy that in our clinical material (in contrast to ERα) the expression of the ERβ in tumor tissues of patients with BRCA1
gene mutations is almost as frequent as in the non-hereditary breast cancer patients. It would be interesting to test whether frequent representation of ERβ in BRCA
-positive tumors is actually responsible for the earlier reported activity of tamoxifen in the reduction of contralateral breast cancer risk.
Fan et al. showed that there is a link between estrogen receptors and the BRCA1 protein. In an in vitro
study, BRCA1 protein proved to be one of the transcription regulators for active ERα. The transcription co-activator p300 plays an important role in this process, and its presence correlates with the ability of the BRCA1 protein to suppress the activation of ERα transcription [7
Our study group displayed certain characteristics of hereditary breast cancer. One of these features was the young age of the patients. In this group, the average age of breast cancer diagnosis was 45 years, 12 years earlier than in the control group. The same average age at which the diagnosis was established, was reported for Spanish families and a similar age (43 years) in Markus's study of the population of Ashkenazi Jews [10
]. Age is a well known factor influencing the expression of ERα. The fact that there was a 12-year difference in the average age between the BRCA1
gene mutations group and the control group must have some influence on the reported ERα expression in our study. Regarding ERβ expression, however, we believe that difference bears no material significance on the result. Our opinion is based on the fact that numerous studies have indicated that the expression of ERβ is not age-dependent.
In both groups, the most frequent histological diagnosis was that of ductal carcinoma (87% and 85.8%, respectively). Another common histological type of breast cancer found in the mutation carriers group was "medullary like" carcinoma (10%). In the control group, however, not a single case of that type of cancer was identified. A higher rate of "medullary like" carcinoma is typical of BRCA1
mutation carriers and this diagnosis is associated with a relatively good prognosis [34
]. Consequently, it was believed that this diagnosis positively affected the prognosis for BRCA1
-positive patients. Unfortunately, a recent study failed to confirm that finding [36
Patients with hereditary disease have been found to develop bilateral breast cancer more often. Our study has confirmed this observation as it has been found that bilateral breast cancer affected 13 patients of the study group (27.1%).
The above characteristics of hereditary breast cancer have been frequently described in the literature and are consistent with the previously published data. Little, however, has been said regarding the expression of ERβ. This appears to have been mentioned only once in a letter to the Editor of the Journal of Clinical Oncology which reported on estrogen receptor-beta expression in hereditary breast cancer where positive staining for ERβ was detectable in 94% (15 of 16) of BRCA1
associated breast cancers [37
In our study, ERβ expression was present in 42% of BRCA1 mutation carriers. This seems to be important as it may explain the protective effect of tamoxifen in the prevention of contralateral tumor development in BRCA1 mutation carriers.
Out of the hereditary cancer patients in our study group, 75% were found to be triple-negative, lacking ERα, PgR and HER-2 over-expression. Unfortunately, at the current state of the art, neither hormonal therapy, nor immunotherapy (trastuzumab) in an adjuvant setting, can be offered to those patients.
Gruvberger-Saal et al [38
] reported that the expression of ERβ is an independent marker for favourable prognosis after adjuvant tamoxifen treatment in ERα negative breast cancer patients. Bearing in mind that as many as 44% of the triple-negative patients in our study expressed ERβ, we propose that hormone therapy might be used in the treatment of BRCA1
mutation carriers expressing the ERα(-)/PgR(-/HER2(-)/ERβ(+) phenotype.
The results obtained in our study show that the expression of ERβ in BRCA1 gene mutation carriers is statistically higher than the expression of ERα. This may be why tamoxifen has proven to be effective in preventing the development of contralateral breast cancer in BRCA1 mutation carriers. Consequently, testing patients carrying BRCA1 mutations for the presence of ERβ might help to identify those who could benefit from endocrine therapy.