The hypoxia-ERα epigenetic axis and its pharmacological inhibition in breast cancer

Breast cancer is the second leading cause of cancer death in women. 70 - 80 % of breast tumours are oestrogen receptor-α (ERα) positive (ER+). Previously, stabilisation of hypoxia-inducible factors (HIF-1 and HIF-2) by DMOG or CoCl2 has reprogrammed the ERα cistrome. This ERα-HIF cross-talk contributes to therapy resistance in ER+ BC and is correlated with poor survival. However, the mechanism of this ERα cistrome reprogramming is poorly understood. Palbociclib is a well-established CDK inhibitor used to treat ER+ BC, which has been reported to downregulate HIF-1α levels in CRC and triple-negative BC. I hypothesised Palbociclib would reduce HIF-1α and -2α expression in ER+ BC, and thus could limit HIF-driven reprogramming of the ERα cistrome. In MCF-7 and T-47D cells, 10 µM Palbociclib downregulated HIF-1α and HIF-2α after 8 and 48 hours of 1% O2, respectively. However, palbociclib treatment did not limit hypoxia-driven changes in ERα-binding to the TFF1 or GREB1 enhancer, suggesting reprogramming is not entirely dependent on HIF, or that Palbociclib-mediated downregulation of HIF is insufficient to disrupt hypoxic reprogramming of the ERα cistrome. Additionally, hypoxic reprogramming of the ERα is also independent of changes in the active marks H3K27ac and H3K4me1 in MCF-7 cells. Further mechanistic studies are thus required to elucidate how ERα reprogramming occurs. Nevertheless, this thesis has demonstrated a novel potential role for Palbociclib as a HIF inhibitor, possibly identifying the first clinical-approved HIF-inhibitor for use in BC.