Highlights d NF1 is a GAP-independent estrogen receptor transcription co-repressor d Somatic NF1 loss causes tamoxifen/aromatase inhibitor resistance in ER + breast cancer d A MEK inhibitor plus a SERD is effective in NF1 -ER + PDX and cell line models
Approximately 75% of breast cancers are estrogen receptor alpha (ERα)-positive and are treatable with endocrine therapies, but often patients develop lethal resistant disease. Frequent mutations (10–40%) in the ligand-binding domain (LBD) codons in the gene encoding ERα (ESR1) have been identified, resulting in ligand-independent, constitutively active receptors. In addition, ESR1 chromosomal translocations can occur, resulting in fusion proteins that lack the LBD and are entirely unresponsive to all endocrine treatments. Thus, identifying coactivators that bind to these mutant ERα proteins may offer new therapeutic targets for endocrine-resistant cancer. To define coactivator candidate targets, a proteomics approach was performed profiling proteins recruited to the two most common ERα LBD mutants, Y537S and D538G, and an ESR1-YAP1 fusion protein. These mutants displayed enhanced coactivator interactions as compared to unliganded wild-type ERα. Inhibition of these coactivators decreased the ability of ESR1 mutants to activate transcription and promote breast cancer growth in vitro and in vivo. Thus, we have identified specific coactivators that may be useful as targets for endocrine-resistant breast cancers.
A subset of environmental chemicals acts as “obesogens” as they increase adipose mass and lipid content in livers of treated rodents. One of the most studied class of obesogens are the tin-containing chemicals that have as a central moiety tributyltin (TBT), which bind and activate two nuclear hormone receptors, Peroxisome Proliferator Activated Receptor Gamma (PPARG) and Retinoid X Receptor Alpha (RXRA), at nanomolar concentrations. Here, we have tested whether TBT chloride at such concentrations may affect the neutral lipid level in two cell line models of human liver. Indeed, using high content image analysis (HCA), TBT significantly increased neutral lipid content in a time- and concentration-dependent manner. Consistent with the observed increased lipid accumulation, RNA fluorescence in situ hybridization (RNA FISH) and RT-qPCR experiments revealed that TBT enhanced the steady-state mRNA levels of two key genes for de novo lipogenesis, the transcription factor SREBF1 and its downstream enzymatic target, FASN. Importantly, pre-treatment of cells with 2-deoxy-D-glucose reduced TBT-mediated lipid accumulation, thereby suggesting a role for active glycolysis during the process of lipid accumulation. As other RXRA binding ligands can promote RXRA protein turnover via the 26S proteasome, TBT was tested for such an effect in the two liver cell lines. We found that TBT, in a time- and dose-dependent manner, significantly reduced steady-state RXRA levels in a proteasome-dependent manner. While TBT promotes both RXRA protein turnover and lipid accumulation, we found no correlation between these two events at the single cell level, thereby suggesting an additional mechanism may be involved in TBT promotion of lipid accumulation, such as glycolysis.
Objectives: Improved intraoperative visibility during functional endoscopic sinus surgery (FESS) decreases the risk of serious orbital or skull base injuries. Esmolol and labetalol have been used to reduce bleeding and achieve better visibility, but it remains unclear which drug is more effective. This study aims to measure visibility scores and mucosal bleeding rates for esmolol and labetalol in FESS. Methods: This is a 1-year randomized double-blind trial of adults undergoing FESS at a tertiary academic center. The inclusion criteria were as follows: age 18 or older; history of chronic rhinosinusitis (CRS) with or without nasal polyps; undergoing FESS for CRS; and American Society of Anesthesiologists (ASA) physical status 1 (healthy) or 2 (patient with mild systemic disease). The exclusion criteria were as follows: pregnancy; asthma, chronic obstructive pulmonary disease (COPD), bradycardia, heart failure, end-stage renal disease, cerebrovascular accident, diabetes mellitus; preoperative use of nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, or beta-blockers; and body mass index (BMI) greater than 40 kg/m 2 . Patients received either dose-infused esmolol or intravenous push labetalol. The primary outcome was intraoperative visibility determined by surgeon using validated scoring systems (Boezaart, Wormald). The secondary outcome was hemodynamic control (rate of blood loss, average mean arterial pressure [MAP], average heart rate [HR]). Hypothesis of no difference between drugs formed before data collection. Results: Of the 32 adults given drug (mean age = 50), 28 patients (13 esmolol and 15 labetalol) with complete data were included in the final analysis. There were no statistically significant differences between esmolol and labetalol in rate of blood loss (0.59 [0.28] vs 0.66 [0.37] mL/min, P = 0.62), average MAP (79.7 [7.5] vs 79.4 [7.7] mm Hg, P = .93), HR (72 [8.7] vs 68 [11.7] bpm, P = .26), or mean visibility scores for the Boezaart (3.1 [0.69] vs 3.1 [0.89], P = .85) and Wormald (6.1 [1.7] vs 5.9 [1.9], P = .72) grading scales. Conclusions: There were no significant differences between esmolol and labetalol in rate of blood loss, MAP control, HR, or surgical visibility in FESS. Either drug may be used, and other considerations (availability, cost) can dictate choice.
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