Anastrozole Regulates Fatty Acid Synthase in Breast Cancer.

Our previous matched case-control study of postmenopausal women with resected early-stage breast cancer revealed that only anastrozole, but not exemestane or letrozole, showed a significant association between the 6-month estrogen concentrations and risk of breast cancer. Anastrozole, but not exemestane or letrozole, is a ligand for estrogen receptor α. The mechanisms of endocrine resistance are heterogenous and with the new mechanism of anastrozole, we have found that treatment of anastrozole maintains fatty acid synthase (FASN) protein level by limiting the ubiquitin-mediated FASN degradation, leading to increased breast cancer cell growth. Mechanistically, anastrozole decreases the guided entry of tail-anchored proteins factor 4 (GET4) expression, resulting in decreased BCL2-associated athanogene cochaperone 6 (BAG6) complex activity, which in turn, prevents RNF126-mediated degradation of FASN. Increased FASN protein level can induce a negative feedback loop mediated by the MAPK pathway. High levels of FASN are associated with poor outcome only in patients with anastrozole-treated breast cancer, but not in patients treated with exemestane or letrozole. Repressing FASN causes regression of breast cancer cell growth. The anastrozole-FASN signaling pathway is eminently targetable in endocrine-resistant breast cancer.

Pharmacogenomics of aromatase inhibitors in postmenopausal breast cancer and additional mechanisms of anastrozole action.

Aromatase inhibitors (AIs) reduce breast cancer recurrence and prolong survival, but up to 30% of patients exhibit recurrence. Using a genome-wide association study of patients entered on MA.27, a phase III randomized trial of anastrozole versus exemestane, we identified a single nucleotide polymorphism (SNP) in CUB And Sushi multiple domains 1 (CSMD1) associated with breast cancer-free interval, with the variant allele associated with fewer distant recurrences. Mechanistically, CSMD1 regulates CYP19 expression in an SNP- and drug-dependent fashion, and this regulation is different among 3 AIs: anastrozole, exemestane, and letrozole. Overexpression of CSMD1 sensitized AI-resistant cells to anastrozole but not to the other 2 AIs. The SNP in CSMD1 that was associated with increased CSMD1 and CYP19 expression levels increased anastrozole sensitivity, but not letrozole or exemestane sensitivity. Anastrozole degrades estrogen receptor α (ERα), especially in the presence of estradiol (E2). ER+ breast cancer organoids and AI- or fulvestrant-resistant breast cancer cells were more sensitive to anastrozole plus E2 than to AI alone. Our findings suggest that the CSMD1 SNP might help to predict AI response, and anastrozole plus E2 serves as a potential new therapeutic strategy for patients with AI- or fulvestrant-resistant breast cancers.

A Robust and Efficient Feature Selection Algorithm for Microarray Data.

In the past decades, a few synergistic feature selection algorithms have been published, which includes Cooperative Index (CI) and K-Top Scoring Pair (k-TSP). These algorithms consider the synergistic behavior of features when they are included in a feature panel. Although promising results have been shown for these algorithms, there is lack of a comprehensive and fair comparison with other feature selection algorithms across a large number of microarray datasets in terms of classification accuracy and computational complexity. There is a need in evaluating their performance and reducing the complexity of such algorithms. We compared the performance of synergistic feature selection algorithms with 11 other commonly used algorithms based on 22 microarray gene expression binary class datasets. The evaluation confirms that synergistic algorithms such as CI and k-TSP will gradually increase the classification performance as more features are used in the classifiers. Also, in order to cut down computational cost, we proposed a new feature selection ranking score called Positive Synergy Index (PSI). Testing results show that features selected using PSI as well as synergistic feature selection algorithms provide better performance compared to with all other methods, while PSI has a computational complexity significantly lower than that of other synergistic algorithms.