ODP556 Krüppel-like factor 9 (KLF9) Links Hormone Dysregulation and Circadian Disruption to Breast Cancer Pathogenesis

Abstract

Abstract Circadian disruption is an emerging driver of breast cancer (BCa), with epidemiological studies linking shift work, chronic jet lag, and undue exposure to light at night to increased cancer risk. Indeed, several clock genes participate in the gating of mitotic entry, regulation of DNA damage response, metabolite sensing, and epithelial-to-mesenchymal transition, thus impacting BCa etiology. Dysregulated estrogen (E2) and glucocorticoid (GC; hydrocortisone, CORT) signaling prevalent in BCa may further contribute to clock desynchrony by directly impacting the expression and cycling dynamics of genes comprising the local breast oscillator. In this study, we identified the tumor suppressor gene, KLF9, as an important point of crosstalk between hormone signaling and the circadian molecular network and further established its functional role in BCa. We determined that KLF9is a direct GC receptor (GR) target gene in mammary epithelial cells, and that induction is likely mediated through coordinate transcriptional activation from multiple CORT-responsive enhancers in the KLF9 locus. Interestingly, the clock-controlled rhythmic expression of KLF9observed in normal MCF10A cells was abolished in the highly aggressive TNBC MDA-MB-231 line. As a transcription factor, in turn, KLF9 modulated the baseline mRNA levels of several clock genes and influenced the GC/E-induced alterations in clock gene expression indicating that KLF9 may function as a feedback regulator of the core clock machinery. We then characterized the functional role of KLF9 in context of the hormone-circadian axis in BCa using cellular assays on survival, proliferation, apoptosis, and migration. We determined that KLF9 plays a tumor-suppressive role in BCa regardless of molecular subtype. In addition, KLF9 overexpression potentiated the anti-tumorigenic effects of CORT in ER+ luminal MCF7 cells, while it played a converse effect in triple-negative MCF10A and MDA-MB-231 cells by restraining CORT-enhanced proliferation and survival. Taken together, our findings suggest that dysregulation of KLF9expression and oscillation in BCa may impinge on circadian network dynamics, thus ultimately aggravating BCa oncogenic landscape. Presentation: No date and time listed