Downregulation of FOXO1 mRNA levels predicts treatment failure in patients with endometrial pathology conservatively managed with progestin-containing intrauterine devices

• We analyzed hormone receptor levels/activity following progestin-containing IUD.
• PR target gene FOXO1 was significantly downregulated in patients who progressed.
• FOXO1 mRNA levels may reflect PR function and response to progestin-based therapy.

ObjectiveTo examine hormone receptor expression levels and downstream gene activation in pre-treatment and post-treatment biopsies in a cohort of patients with endometrial pathology who were being conservatively managed with a progestin-containing intrauterine device (IUD). A molecular signature of treatment failure is proposed.MethodsA retrospective analysis of pre- and post-treatment biopsy specimens from 10 women treated with progestin-containing IUD for complex atypical hyperplasia (CAH) or grade 1 endometrioid adenocarcinoma was performed. Expression of estrogen receptor (ER), progesterone receptor (PR) and PR target genes was examined by immunohistochemistry (IHC) and quantitative RT-PCR.ResultsThe mean treatment duration was 14.3 months. Four CAH patients had stable disease or regressed after treatment, and four progressed to endometrioid adenocarcinoma. Both patients with an initial diagnosis of endometrioid adenocarcinoma regressed to CAH or no disease. In general, hormone receptor levels diminished post-treatment compared to pre-treatment biopsies; however, we noted unexpected higher expression of the B isoform of PR (PRB) as well as ER in those patients who progressed to frank cancer. There was a trend towards a non-nuclear cytoplasmic location of PRB in these patients. Importantly, the differentiating impact of PR signaling, as determined by the expression of the progestin-controlled tumor suppressor FOXO1, was lost in individuals who progressed on therapy.ConclusionsFOXO1 mRNA levels may serve as a biomarker for response to therapy and an indicator of PR function in patients being conservatively managed with a progestin-containing IUD.