Oral Presentation Annual Meetings of the Endocrine Society of Australia and Society for Reproductive Biology and Australia and New Zealand Bone and Mineral Society 2016

Emerging role of orphan NRs in breast cancer: new therapeutic targets (#159)

George Muscat 1 , David Gallego Ortega 2 , Tae Gyu Oh 1 3 , Shu Ching Wang 1 3
  1. University of Queensland, Institute for Molecular Biosciences, Brisbane, QLD, Australia
  2. CANCER DIVISION, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  3. University of Queensland, Brisbane, QLD, Australia

Breast cancer is the most common cause of cancer-related death in women, and accounts for ~25-30% of new cancers in Australian women. The expression of estrogen and progesterone receptors (ER and PR) has been the foundation of disease diagnosis, and treatment. However, triple negative and basal subtype cancers are often resistant to current therapeutic regimes and associated with poor survival outcomes, underscoring the need to identify novel therapeutic targets. Previously, we demonstrated differential expression of the entire NR superfamily of 48, in ER+ve and ER-ve breast cancer, relative to normal breast, that underscored the therapeutic and prognostic potential of NRs. One feature of the analysis was the negative association between the orphan NRs, RORγ and NUR77, and histological grade. We report triple negative and basal subtype tumours display decreased RORγ and Nur77 expression, and increased RORγ and Nur77 expression are associated with improved survival outcomes. RNA-seq coupled to bioinformatic analysis demonstrated that RORγ attenuates the oncogenic TGF-β/EMT and mammary stem cell (MaSC) pathways, whereas RORγ positively regulates DNA-repair. Moreover, RORγ expression is inversely correlated with drivers of carcinogenesis. Furthermore, integration of RNA-seq and ChIP-chip data revealed that RORγ regulates the expression of many genes (including lncRNAs) driving carcinogenesis. LncRNAs regulate transcription, and our current studies are focused on several (RORγ-dependent) lncRNAs, that are significantly expressed in aggressive ER-ve basal cancer lines, are increased in the metastatic breast cancer subtypes and display significant correlation with coding genes that effect clinical outcomes. In the context of Nur77, we are utilizing mammary specific Nur77 transgenic mice, and crossing with the MMTV-PyMT mouse model of mammary tumourigenesis to examine the effects on the onset, incidence and progression of mammary tumourigenesis. Initial in vitro drug studies and preclinical mouse studies suggest pharmacological exploitation of orphan NRs may have utility in breast cancer.