Gene signatures of estrogen and progesterone receptor pathways predict the prognosis of colorectal cancer

• Published in: The FEBS journal 2016-08, Vol.283 (16), p.3115-3133
• Main Author: Liu, Dingxie
• Format: Article
• Language: English
• Subjects: Adenoma - genetics; Adenoma - metabolism; Biomarkers; Chemotherapy, Adjuvant; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Disease-Free Survival; Down-Regulation; estrogen receptor pathway; Estrogens; Gene Expression Profiling; gene signature; Genes; Hormones; Humans; Intestinal Mucosa - metabolism; Medical prognosis; microsatellite instability; Neoplasm Recurrence, Local; progesterone receptor pathway; Prognosis; prognosis prediction; Receptors, Estrogen - metabolism; Receptors, Progesterone - metabolism
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.13798

The associations of estrogen receptor (ER) and progesterone receptor (PR) pathways with the prognosis of colorectal cancer (CRC) are still controversial. The aim of this study was to readdress these issues by introducing a gene signature‐based approach to semiquantitate pathway activity. In this approach, the ER and PR pathway activities in CRC were computed based on the expression profiles of the signature genes of ER and PR pathways, respectively. The results showed that the ER pathway activity was progressively significantly decreased from normal colorectal mucosa, colorectal adenoma to CRC. ER pathway signaling was a favorable factor for the presence of microsatellite stability (MSS) in CRC in seven cohorts tested, while was an unfavorable factor for cancer recurrence in all four CRC cohorts tested (n = 1122; overall HR: 0.311, 95% CI: 0.199–0.488, P < 0.001). Subset stratification in stage II patients showed that ER pathway remained significantly inversely associated with recurrence. PR pathway was also suppressed in colorectal tumors and inversely associated with recurrence of CRC, but to a much lesser extent than ER pathway. Moreover, the inverse association of PR pathway with cancer recurrence was more likely observed in CRC with high ER pathway activity, suggesting the interactions between the two pathways. PR pathway was not associated with MSS in CRC, but it was more significant than ER pathway associated with advance cancer stages and cancer response to adjuvant chemotherapy. These results suggested the potential application of the gene signatures of ER and PR pathways, especially the former, as novel markers for prognosis and management of CRC. To clarify the controversial associations of ER and PR pathways with the prognosis of CRC, a novel gene signature‐based approach was employed to semiquantitate the activities of these two pathways in CRC samples. The results indicate that the down‐regulation of these two pathways, especially ER pathway, is common in CRC and significantly associated with recurrence risk of this cancer.