High BRCA1 Gene Expression Increases the Risk of Early Onset Distant Metastasis in ER+ Breast Cancers

Abstract BackgroundMore than 30% of ER+ breast cancer patients developed distant metastasis after adjuvant tamoxifen therapy. It has been shown that decreased BRCA1 protein function confers anti-estrogen “resistance.” Since the functional status of BRCA1 protein auto-regulates its own gene expression, BRCA1 transcript level should possibly be used to assess its active protein levels. Thus, it is interesting to explore the potential links between BRCA1 gene expression status and the prognosis of ER+ breast tumors.MethodsEarly-staged ER+ Breast cancer microarray samples were selected from the NCBI Gene Expression Omnibus (GEO) database. The aggressiveness of these tumors was evaluated based on molecular subtypes or patients’ distant metastasis-free survival (DMFS) time found in associated GEO datasets. In survival analysis, the optimal threshold to define high and low transcript levels was assessed by the logistic-accelerated failure time mixture regression model in a pooled data set, which simultaneously envisages the lifetime risk of distant metastasis and the distribution of the DMFS time from the surgery of a patient susceptible to distant metastasis. ResultsOn the basis of molecular subtyping, the relatively aggressive Luminal B tumor cells expressed significantly more BRCA1 transcripts than the less aggressive Luminal A tumor cells. This observation was supported by DMFS time analysis. When the upper 10% of the high BRCA1 expression patients was compared with the rest of the patients, the result was quite drastic. In patients susceptible to distant metastasis, the median onset time of distant metastasis for high BRCA1 expression group (2.2 years) was about one-fifth of the BRCA1 low expression group (10.5 years).ConclusionsHigh BRCA1 transcript level does not increase the incidence of distant metastasis, but increases the risk of early onset distant metastasis in ER+ breast cancers. As new therapeutic drugs have been developed for tumors with BRCA function loss, our findings suggest that BRCA1 gene expression test not only is useful for predicting patients’ outcome but also can be used in treatment decision.