Elucidating the role of the nuclear hormone receptor RORy1 in breast cancer (2016–2018)
Abstract:
The nuclear hormone receptor (NR) superfamily are hormone dependent transcription factors that translate physiological signals into gene regulation. The significance of the NR superfamily implicated in health (&disease) is underscored by the efficacy of pharmaceuticals that account for ~15% of FDA approvals and target NRs/dysfunctional hormone signalling for the treatment of endocrine and reproductive disorders, cancer, inflammation etc. We have demonstrated the NR superfamily is differentially expressed in ER+ and ER - breast cancer, relative to normal breast, and display discriminant, therapeutic and prognostic value in breast pathophysiology. Breast cancer is the most common invasive cancer and cause of cancer-related death in Australian women. Increasing numbers of studies indicate the involvement of aberrant nuclear hormone receptor signalling in breast cancer. Our data provides a compelling argument for studying the NR, ROR¿¿1, in breast cancer. For example, ROR¿¿ expression was decreased in ER-ve breast cancer, and was negatively associated with histological grade, and increased ROR¿¿ expression improved the probability of metastasis free survival. However, the role of ROR¿¿ (associated with the emergence of small molecule regulators) in the underlying molecular and cellular mechanisms controlling carcinogenesis and the onset/incidence and growth of breast cancer/tumours remains obscure. Accordingly, the aims include ROR¿¿ gain & loss of function analysis in breast cancer cells, coupled to RNA&ChIP-seq. analysis to examine ROR¿¿ dependent signalling, and the predictive/prognostic value of ROR¿¿-dependent gene signatures on survival. Moreover, additional aims will test the hypothesis that genetic & pharmacological modulation of ROR¿¿ signalling regulates: (i) cell proliferation, self renewal , migration, invasion, metastasis and genome stability , and (ii) regulates the onset, growth, progression and metastasis of mammary tumourigenesis i...
