The Evolution of Estrogen Receptor Signaling in the Progression of Endometriosis to Endometriosis-Associated Ovarian Cancer
To investigate changes in estrogen receptor alpha (ERα) signaling during progression of endometriosis to endometriosis-associated ovarian cancer (EAOC) as a driver of malignant transformation. We procured tissue samples of normal endometrium, endometriosis (benign, atypical, concurrent with EAOC), and EAOC. We evaluated expression of a 236-gene signature of estrogen signaling. ANOVA and unsupervised clustering were used to identify gene expression profiles across disease states. These profiles were compared to profiles of estrogen regulation in cancer models from the Gene Expression Omnibus (GEO). Gene Set Enrichment Analysis (GSEA) was performed to determine whether gene expression in EAOC was consistent with ERα activity. ANOVA revealed 158 differentially expressed genes (q < 0.05) and unsupervised clustering identified five distinct gene clusters. The estrogen signaling profile of EAOC was not consistent with activated ERα in pre-clinical models. Gene set enrichment analysis did not identify signatures of activated ERα in EAOC but instead identified expression patterns consistent with loss of ERα function and development of endocrine resistance. Gene expression data suggest that ERα signaling becomes inactivated throughout the progression of endometriosis to EAOC. The gene expression pattern in EAOC is more consistent with profiles of endocrine resistance.
KeywordsEndometriosis Estrogen receptor alpha Human Estrogens Ovarian neoplasms Transcriptome
This study was supported by the UPMC Research Fund (to R. Edwards and A.M. Vlad). C. L. Andersen was supported by F31CA186376, T32GM008424, and the ARCS Foundation. M.J. Sikora was supported by K99CA193734.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
- 4.Pearce CL, Templeman C, Rossing MA, Lee A, Near AM, Webb PM, Nagle CM, Doherty JA, Cushing-Haugen KL, Wicklund KG, Chang-Claude J, Hein R, Lurie G, Wilkens LR, Carney ME, Goodman MT, Moysich K, Kjaer SK, Hogdall E, Jensen A, Goode EL, Fridley BL, Larson MC, Schildkraut JM, Palmieri RT, Cramer DW, Terry KL, Vitonis AF, Titus LJ, Ziogas A, Brewster W, Anton-Culver H, Gentry-Maharaj A, Ramus SJ, Anderson AR, Brueggmann D, Fasching PA, Gayther SA, Huntsman DG, Menon U, Ness RB, Pike MC, Risch H, Wu AH, Berchuck A, Ovarian Cancer Association Consortium (2012) Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case-control studies. Lancet Oncol 13:385–394CrossRefGoogle Scholar
- 5.Suryawanshi S, Vlad AM, Lin HM, Mantia-Smaldone G, Laskey R, Lee M, Lin Y, Donnellan N, Klein-Patel M, Lee T, Mansuria S, Elishaev E, Budiu R, Edwards RP, Huang X (2013) Plasma microRNAs as novel biomarkers for endometriosis and endometriosis-associated ovarian cancer. Clin Cancer Res 19:1213–1224CrossRefGoogle Scholar
- 7.Suryawanshi S, Huang X, Elishaev E, Budiu RA, Zhang L, Kim S, Donnellan N, Mantia-Smaldone G, Ma T, Tseng G, Lee T, Mansuria S, Edwards RP, Vlad AM (2014) Complement pathway is frequently altered in endometriosis and endometriosis-associated ovarian cancer. Clin Cancer Res 20:6163–6174CrossRefGoogle Scholar
- 12.Collaborative Group on Epidemiological Studies of Ovarian C, Beral V, Doll R, Hermon C, Peto R, Reeves G (2008) Ovarian cancer and oral contraceptives: collaborative reanalysis of data from 45 epidemiological studies including 23,257 women with ovarian cancer and 87,303 controls. Lancet 371:303–314CrossRefGoogle Scholar
- 14.Andersen CL, Sikora MJ, Boisen MM, Ma T, Christie A, Tseng G, Park Y, Luthra S, Chandran U, Haluska P, Mantia-Smaldone GM, Odunsi K, McLean K, Lee AV, Elishaev E, Edwards RP, Oesterreich S (2017) Active estrogen receptor-alpha signaling in ovarian cancer models and clinical specimens. Clin Cancer Res 23:3802–3812CrossRefGoogle Scholar
- 19.Sikora MJ, Cooper KL, Bahreini A, Luthra S, Wang G, Chandran UR, Davidson NE, Dabbs DJ, Welm AL, Oesterreich S (2014) Invasive lobular carcinoma cell lines are characterized by unique estrogen-mediated gene expression patterns and altered tamoxifen response. Cancer Res 74:1463–1474CrossRefGoogle Scholar
- 22.Stossi F, Barnett DH, Frasor J, Komm B, Lyttle CR, Katzenellenbogen BS (2004) Transcriptional profiling of estrogen-regulated gene expression via estrogen receptor (ER) alpha or ERbeta in human osteosarcoma cells: distinct and common target genes for these receptors. Endocrinology 145:3473–3486CrossRefGoogle Scholar
- 34.Turner N, Pearson A, Sharpe R, Lambros M, Geyer F, Lopez-Garcia MA, Natrajan R, Marchio C, Iorns E, Mackay A, Gillett C, Grigoriadis A, Tutt A, Reis-Filho JS, Ashworth A (2010) FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res 70:2085–2094CrossRefGoogle Scholar