BRCA1 Modulation of Glucocorticoid Receptor Signal Signaling in High-grade Serous Ovarian Cancer Cells

Germline BRCA1 mutations increase a woman’s risk of developing high-grade serous ovarian cancer (HGSOC) up to 43-fold. Lifetime ovulatory events also associate with increased risk. Studies suggest the post-ovulatory pro-inflammatory milieu persists longer in BRCA1 mutation carriers compared to control women. Slowed remediation of pro-inflammatory signaling leads to increased reactive oxygen species levels that potentiate DNA damage accumulation, which may ultimately promote malignant transformation. Preliminary evidence suggests BRCA1 may modulate glucocorticoid receptor (GR) activity, a major anti-inflammatory mediator. Impairment of GR signaling by BRCA1 mutation may contribute to increased HGSOC risk. My objective was to determine if BRCA1 deficiency affects GR signaling in HGSOC cells. My results indicate BRCA1 enhances GR levels and GR transcriptional activity independent of its effect on GR levels. BRCA1 expression also correlates with diminished pro-inflammatory cytokine mRNA levels at baseline. Overall, BRCA1 has a dynamic role in modulating inflammatory signaling through GR in HGSOC cells.M.Sc.2018-03-15 00:00:0