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Abstract Background The mutational processes underlying non-coding cancer mutations and their biological significance in tumor evolution are poorly understood. To get better insights into the biological mechanisms of mutational processes in breast cancer, we integrate whole-genome level somatic mutations from breast cancer patients with chromatin states and transcription factor binding events. Results We discover that a large fraction of non-coding somatic mutations in estrogen receptor (ER)-positive breast cancers are confined to ER binding sites. Notably, the highly mutated estrogen receptor binding sites are associated with more frequent chromatin loop contacts and the associated distal genes are expressed at higher level. To elucidate the functional significance of these non-coding mutations, we focus on two of the recurrently mutated estrogen receptor binding sites. Our bioinformatics and biochemical analysis suggest loss of DNA-protein interactions due to the recurrent mutations. Through CRISPR interference, we find that the recurrently mutated regulatory element at the LRRC3C-GSDMA locus impacts the expression of multiple distal genes. Using a CRISPR base editor, we show that the recurrent C→T conversion at the ZNF143 locus results in decreased TF binding, increased chromatin loop formation, and increased expression of multiple distal genes. This single point mutation mediates reduced response to estradiol-induced cell proliferation but increased resistance to tamoxifen-induced growth inhibition. Conclusions Our data suggest that ER binding is associated with localized accumulation of somatic mutations, some of which affect chromatin architecture, distal gene expression, and cellular phenotypes in ER-positive breast cancer.

Hypertension causes significant mortality and morbidity around the world. The β-adrenergic blockers are one of the most commonly prescribed hypertension medications. Several β-adrenergic blockers with different pharmacological qualities have been developed, which may be grouped into three generations based on the differences in pharmacological properties. In this narrative review, we addressed evidence-based literature about the role of various types of β-blockers and related adverse drug reactions (ADRs) in hypertension. PubMed, Scopus, Google Scholar, and MEDLINE are used for articles search. The title was examined first, followed by the abstract, and then the entire study. We concluded that the first-generation β-blockers are non-selective and used as antihypertensive however, not recommended for diabetic, asthmatic, and chronic obstructive pulmonary disease patients. The second-generation β-blockers are β1 receptor-selective which are the effective pharmacological option for the treatment of hypertension, with a lower risk of adverse effects associated with antagonism of β2-receptor. Third-generation β-blockers showed improved effects on patients as compared to the previous two generations. This class of β-blockers (labetalol, carvedilol, and nebivolol) has vasodilatory abilities and has an extra beneficial influence with fewer ADRs. However, the effectiveness and benefit of β-blockers as first‐line therapy for hypertension is still controversial. As a result, further accurate screenings, as well as large randomized control clinical trials (RCTs), are needed to investigate the role of all β-blockers in hypertension. Keywords: Hypertension; Beta-Adrenergic Blockers; Blood Pressure; Literature Review.