Abstract
Since BRCA1 associated breast cancers are frequently classified as hormone receptor negative or even triple negative, the application of endocrine therapies is rather limited in these patients. Like hormone receptors that bind to estrogen or progesterone, thyroid hormone receptors (TRs) are members of the nuclear hormone receptor superfamily. TRs might be interesting biomarkers - especially in the absence of classical hormone receptors. The current study aimed to investigate whether TRs may be specifically expressed in BRCA1 associated cancer cases and whether they are of prognostic significance in these patients as compared to sporadic breast cancer cases. This study analyzed TRα and TRβ immunopositivity in BRCA1 associated (n = 38) and sporadic breast cancer (n = 86). Further, TRs were studied in MCF7 (BRCA1 wildtype) and HCC3153 (BRCA1 mutated) cells. TRβ positivity rate was significantly higher in BRCA1 associated as compared to sporadic breast cancers (p = 0.001). The latter observation remained to be significant when cases that had been matched for clinicopathological criteria were compared (p = 0.037). Regarding BRCA1 associated breast cancer cases TRβ positivity turned out to be a positive prognostic factor for five-year (p = 0.007) and overall survival (p = 0.026) while TRα positivity predicted reduced five-year survival (p = 0.030). Activation of TRβ resulted in down-modulation of CTNNB1 while TRα inhibition reduced cell viability in HCC3153. However, only BRCA1 wildtype MCF7 cells were capable of rapidly degrading TRα1 in response to T3 stimulation. Significantly, this study identified TRβ to be up-regulated in BRCA1 associated breast cancer and revealed TRs to be associated with patients’ prognosis. TRs were also found to be expressed in triple negative BRCA1 associated breast cancer. Further studies need to be done in order to evaluate whether TRs may become interesting targets of endocrine therapeutic approaches, especially when tumors are triple-negative.
Highlights
Breast cancers diagnosed in patients carrying a BRCA1 germline mutation display distinct histo-pathological as well as molecular characteristics and have been observed to differ from sporadic cases regarding chemotherapeutic sensitivity [1]
This work showed TRβ to be more frequently expressed in BRCA1 associated breast cancers as compared to sporadic breast cancer
While a direct link is still missing, thyroid hormones and breast cancer have been associated for quite a while; e. g. an elevated incidence of thyroid dysfunction has been observed in breast cancer patients [26,27,28]
Summary
Breast cancers diagnosed in patients carrying a BRCA1 germline mutation display distinct histo-pathological as well as molecular characteristics and have been observed to differ from sporadic cases regarding chemotherapeutic sensitivity [1]. BRCA1 associated breast cancers display a higher incidence of medullary or basal-like histology and might overexpress cell cycle stimulator genes [2,3,4]. Since patients’ TR statuses can be determined by immunohistochemistry and as TRs were demonstrated to be accessible targets [6,9], TRs might be novel alternative biomarkers, especially for hormone receptor negative or even triple negative breast cancer patients. With a high percentage of BRCA1 associated breast cancers being classified as triple-negative, the assessment of TR expression in those patients may turn out to be attractive in terms of alternative treatment options, applicable especially for breast cancer patients carrying a BRCA1 germline mutation
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