The Molecular Effects of a High Fat Diet on Endometrial Tumour Biology
Michael Wilkinson,
Piriyah Sinclair,
Ludmilla Dellatorre-Teixeira,
Patrick Swan,
Eoin Brennan,
Bruce Moran,
Dirk Wedekind,
Paul Downey,
Kieran Sheahan,
Emer Conroy,
William M. Gallagher,
Neil Docherty,
Carel le Roux,
Donal J. Brennan
Affiliations
Michael Wilkinson
Department of Gynaecological Oncology, UCD School of Medicine, Mater Misericordiae Universtity Hospital, Eccles Street, Dublin 7, D07 AX57 Dublin, Ireland
Piriyah Sinclair
UCD Diabetes Complications Research Centre, UCD Conway Institute, University College Dublin, D14 NN96 Dublin, Ireland
Ludmilla Dellatorre-Teixeira
UCD Diabetes Complications Research Centre, UCD Conway Institute, University College Dublin, D14 NN96 Dublin, Ireland
Patrick Swan
UCD Diabetes Complications Research Centre, UCD Conway Institute, University College Dublin, D14 NN96 Dublin, Ireland
Eoin Brennan
UCD Diabetes Complications Research Centre, UCD Conway Institute, University College Dublin, D14 NN96 Dublin, Ireland
Bruce Moran
Department of Pathology, St Vincent’s University Hospital, Elm Park, Dublin 4, D04 YN63 Dublin, Ireland
Dirk Wedekind
Biomedical Facility, Hanover Medical School, 30625 Hanover, Germany
Paul Downey
Department of Pathology, National Maternity Hospital, Holles Street, Dublin 2, D02 YH21 Dublin, Ireland
Kieran Sheahan
Department of Pathology, St Vincent’s University Hospital, Elm Park, Dublin 4, D04 YN63 Dublin, Ireland
Emer Conroy
Cancer Biology and Therapeutic Laboratory, UCD School of Biomolecular and Biomedical Science Ireland, UCD Conway Institute, University College Dublin, D14 NN96 Dublin, Ireland
William M. Gallagher
Cancer Biology and Therapeutic Laboratory, UCD School of Biomolecular and Biomedical Science Ireland, UCD Conway Institute, University College Dublin, D14 NN96 Dublin, Ireland
Neil Docherty
UCD Diabetes Complications Research Centre, UCD Conway Institute, University College Dublin, D14 NN96 Dublin, Ireland
Carel le Roux
UCD Diabetes Complications Research Centre, UCD Conway Institute, University College Dublin, D14 NN96 Dublin, Ireland
Donal J. Brennan
Department of Gynaecological Oncology, UCD School of Medicine, Mater Misericordiae Universtity Hospital, Eccles Street, Dublin 7, D07 AX57 Dublin, Ireland
We sought to validate the BDII/Han rat model as a model for diet-induced obesity in endometrial cancer (EC) and determine if transcriptomic changes induced by a high fat diet (HFD) in an EC rat model can be used to identify novel biomarkers in human EC. Nineteen BDII/Han rats were included. Group A (n = 7) were given ad lib access to a normal calorie, normal chow diet (NCD) while Group B (n = 12) were given ad lib access to a calorie rich HFD for 15 months. RNAseq was performed on endometrial tumours from both groups. The top-ranking differentially expressed genes (DEGs) were examined in the human EC using The Cancer Genome Atlas (TCGA) to assess if the BDII/Han rat model is an appropriate model for human obesity-induced carcinogenesis. Weight gain in HFD rats was double the weight gain of NCD rats (50 g vs. 25 g). The incidence of cancer was similar in both groups (4/7—57% vs. 4/12—33%; p = 0.37). All tumours were equivalent to a Stage 1A, Grade 2 human endometrioid carcinoma. A total of 368 DEGs were identified between the tumours in the HFD group compared to the NCD group. We identified two upstream regulators of the DEGs, mir-33 and Brd4, and a pathway analysis identified downstream enrichment of the colorectal cancer metastasis and ovarian cancer metastasis pathways. Top-ranking DEGs included Tex14, A2M, Hmgcs2, Adamts5, Pdk4, Crabp2, Capn12, Npw, Idi1 and Gpt. A2M expression was decreased in HFD tumours. Consistent with these findings, we found a significant negative correlation between A2M mRNA expression levels and BMI in the TCGA cohort (Spearman’s Rho = −0.263, p A2M expression was associated with improved overall survival (HR = 0.45, 95% CI 0.23–0.9, p = 0.024). Crabp2 expression was increased in HFD tumours. In human EC, CRABP2 expression was associated with reduced overall survival (HR = 3.554, 95% CI 1.875–6.753, p < 0.001). Diet-induced obesity can alter EC transcriptomic profiles. The BDII/Han rat model is a suitable model of diet-induced obesity in endometrial cancer and can be used to identify clinically relevant biomarkers in human EC.
