The impact of poor metabolic health on aggressive breast cancer: adipose tissue and tumor metabolism.

Obesity and type 2 diabetes are chronic metabolic diseases that impact tens to hundreds of millions of adults, especially in developed countries. Each condition is associated with an elevated risk of breast cancer and with a poor prognosis after treatment. The mechanisms connecting poor metabolic health to breast cancer are numerous and include hyperinsulinemia, inflammation, excess nutrient availability, and adipose tissue dysfunction. Here, we focus on adipose tissue, highlighting important roles for both adipocytes and fibroblasts in breast cancer progression. One potentially important mediator of adipose tissue effects on breast cancer is the fibroblast growth factor receptor (FGFR) signaling network. Among the many roles of FGFR signaling, we postulate that key mechanisms driving aggressive breast cancer include epithelial-to-mesenchymal transition and cellular metabolic reprogramming. We also pose existing questions that may help better understand breast cancer biology in people with obesity, type 2 diabetes, and poor metabolic health.

Nucleolar disruption, activation of P53 and premature senescence in POLR3A-mutated Wiedemann-Rautenstrauch syndrome fibroblasts.

Recently, mutations in the RNA polymerase III subunit A (POLR3A) have been described as the cause of the neonatal progeria or Wiedemann-Rautenstrauch syndrome (WRS). POLR3A has important roles in transcription regulation of small RNAs, including tRNA, 5S rRNA, and 7SK rRNA. We aim to describe the cellular and molecular features of WRS fibroblasts. Cultures of primary fibroblasts from one WRS patient [monoallelic POLR3A variant c.3772_3773delCT (p.Leu1258Glyfs*12)] and one control patient were cultured in vitro. The mutation caused a decrease in the expression of wildtype POLR3A mRNA and POLR3A protein and a sharp increase in mutant protein expression. In addition, there was an increase in the nuclear localization of the mutant protein. These changes were associated with an increase in the number and area of nucleoli and to a high increase in the expression of pP53 and pH2AX. All these changes were associated with premature senescence. The present observations add to our understanding of the differences between Hutchinson-Gilford progeria syndrome and WRS and opens new alternatives to study cell senesce and human aging.