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Endocrine Abstracts (2015) 37 OC8.5 | DOI: 10.1530/endoabs.37.OC8.5

1Monash University, Melbourne, Victoria, Australia; 2Garvan Insitute of Medical Research, Sydney, New South Wales, Australia; 3Karolinska institutet, Stockholm, Sweden; 4University of Adelaide, Adelaide, South Australia, Australia; 5Tissupath Pathology Services, Melbourne, Victoria, Australia.


In human prostate, Oestrogen receptor α (ERα) expression in the epithelium increases with tumour Grade and promotes proliferation involving classical genomic and rapid non-genomic signalling, as well as transcription regulation of non-coding RNA. Similarly, in the tumour stroma there is up-regulation of ERα, corresponding with declining AR, resulting in a higher ratio of ERα:AR with increasing Grade. Additionally, in prostate cancer-associated fibroblasts (CAFs) we reported an oestrogen-regulated gene expression signature and showed CXCL12 (SDF-1) was the most highly over-expressed gene. Functional assays showed that the CXCL12 secreted by CAFs recruits mast cells via CXCR4, with mast cells in turn expressing ERα, activated by oestrogen, and exhibiting altered pro-inflammatory chemokine/cytokine expression in response to oestrogen. To identify the mechanism regulating oestrogen gene expression in stroma, we examined patient-matched CAFs and normal prostate fibroblasts (NPFs) from prostatectomy specimens from a cohort of ten patients. We observed hypomethylation of the promoter of ESR1 gene (encoding ERα), which correlated with a higher ERα mRNA abundance in CAFs vs NPFs. To investigate if there was evidence of a broader role of epigenetic gene regulation, we used whole genome bisulphite sequencing to compile the first complete epigenome map of the human prostate tumour stroma. In addition to ESR1, there were >300 differentially methylated regions, including global hypomethylation and focal hypermethylation, in CAFs vs NPFs. Collectively, these data demonstrate that epigenomic changes in tumour stroma are a mechanism underlying the enduring functional differences between NPFs and CAFs. This includes epigenetically-regulated genes, such as ESR1, that are implicated in prostate cancer progression. These results warrant similar studies to determine if ERα is epigenetically regulated in epithelia, especially in advanced prostate cancer.

Disclosure: National Health & Medical Research Council, ID: 1002648, 1020959, 1035721 & 1003247.

Prostate Cancer Foundation of Australia (Movember), ID: YI0911.

Cancer Australia, ID: 1044458CA.

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