For example, BRCA1 function may be altered by somatic mutation, methyla tion or other genetic alterations, or it may be impaired by incorrect cellular localization. The basal like subtype of breast cancer is associated with lack of expression of the estrogen receptor and poor prognosis. A strong connec tion between the basal like subtype and BRCA1 loss of function has been suggested in a number of molecular and pathological studies. Among the 12 sporadic breast cancer that were misclassified by TST, 7 are basal like . Since there are 14 basal like samples in total, the probability of seeing 7 of them in 12 randomly chosen samples is indeed small. Therefore, the basal like types are over represented in the 12 nonBRCA1 mutant samples which are classified as BRCA1 mutant cancers by TST, arguing for the biological relevance of the top scoring triplet.
The analysis of the protein protein interactions among the top scoring triplet genes and BRCA1 further suggests that the classifier has a biological foundation. No interactors were found for TMEM57, possibly reflecting its role in the classifier as the pivot gene, while the other two genes showed interactions with many other proteins involved in breast cancer biology including the BRCA1 protein itself. classifiers be made as robust as possible by maximizing PPP1CB is one of the three catalytic sub units of the pro tein phosphatase PP1. A 2007 study shows that all three isoforms of PP1 interact with BRCA1. In the same study, RT PCR expression analysis indicates that sporadic breast cancers have lower expression levels of PPP1CB than do normal tissues.
The gene expression microarray data that we use show a higher expression level of PPP1CB in BRCA1 mutant cancers than in sporadic breast cancers. Moreover, the literature also suggests that PPP1CB is a dis criminator gene between BRCA1 mutant and BRCA2 mutant tumors for both breast and ovarian cancers. Although no direct links exist between RNF14 and BRCA1, our PPI AV-951 analysis shows that indirect interactions occur, and they involve important proteins in breast can cer biology, like the estrogen and androgen receptors. The expression of the estrogen receptor is a fundamental prog nostic factor in breast cancer hormonal therapy is used in adjuvant settings based on whether cancer cells express it or not. Androgen receptor signaling is also emerging as a relevant pathway for breast cancer biology.
Unlike pros tate cancer, where AR is sustaining growth of cancer cells, androgen signaling in breast cancer represents a restraint to cancer cell growth, and it has been shown that AR expression correlates with a better prognosis. Inter estingly, reduced or altered BRCA1 protein expression has been shown to be associated with lack of progesterone and ESR1, and expression of the AR. From this per spective, it is important that AR activity is modulated by numerous factors, including RNF14 and BRCA1.