Role of the Hsp90 cochaperone, FKBPL, in oestrogen receptor signalling and breast cancer growth and survival

Excerpt

Hsp90 chaperone complexes are involved in maintaining the stability and signalling of Hsp90 client proteins such as the oestrogen receptor (ER). The ER is the primary mediator of breast cancer proliferation in response to oestrogen. Since increased ER levels and transcriptional activation are associated with over 50% of breast cancers, the ER is an attractive target for cancer treatment strategies. Hsp90 inhibitors such as 17AAG are known to destabilize these complexes by promoting proteasome-mediated degradation of the steroid hormone receptor leading to tumour growth inhibition [1] and sensitization to chemotherapy [2] and radiotherapy [3]. Using protein interaction assays, we have identified FKBPL, a novel gene that codes for an immunophilin-like protein, as an Hsp90 cochaperone associated with the ER and dynein motor protein complex. Overexpression studies have demonstrated that FKBPL modulates ER signalling and affects breast cancer growth and survival. Since most tumours become refractory to current hormonal therapies within a year of starting treatment, FKBPL represents a novel drug target that would enable the disruption of signalling pathways integral in maintaining ER-mediated tumour growth and survival. …