Since TCF7L2, a protein mediating DNA looping for long distance interactions of distal en hancers and proximal promoters, physically interacts with FOXA1 and AR and mediates the transcription of MYC in breast cancer, future investigation will inhibitor Navitoclax be needed to clarify which co regulators are involved in FOXA1 AR binding to the enhancer regions upstream of MYC in EC cells. Although the underlying mechanisms governing the FOXA1 AR correlation in tumor progression are not fully understood, a pathway analysis showed that 187 FOXA1 AR dual target genes were involved in the cellu lar growth proliferation pathway in liver cancer. The Notch pathway is implicated in the development of various cancers, and the Notch pathway blockade ap pears to affect cell proliferation in multiple types of can cers.

Notch pathway inhibition in breast cancer cells induces cell cycle arrest and apoptosis. Similarly, downregulation of Notch1 contributes to cell growth in hibition in pancreatic cancer. Our results suggest that downregulation of AR attenuated FOXA1 induced up regulation of the Notch pathway in EC cells. These findings indicate that FOXA1 might promote AR mediated tran scription and ultimately activate the Notch pathway. Here, we describe, for the first time, the association between FOXA1 expression and the Notch pathway in cancer. The specific mechanism of cell proliferation in EC re ported so far has been limited, although several classical transcription factors related to proliferation have been identified, including cyclin D1, p53, IGFBP 1, PTEN, and p27Kip1.

In this study, we suggest that FOXA1 pro motes cell proliferation in EC by interaction with AR, pos sibly via the Notch pathway, which may be a newly identified regulatory mechanism of cell proliferation in EC. We further investigated the effects of FOXA1 and AR on migration and invasion of EC cells, and found that neutralization of AR activity did not inhibit FOXA1 enhanced cancer cell migration or invasion. These obser vations indicate that the promoting effect of FOXA1 on migration and invasion is not dependent on AR. Our findings in migration and invasion assays are consistent with our findings in immunohistochemical staining, which showed that higher expression of FOXA1 but not AR is found in tumors that displayed a greater depth of myometrial invasion. These results suggest that AR is not the only downstream target of FOXA1 in EC.

Future studies will be necessary to define which transcription factors or pathways are involved in FOXA1 enhanced cell migration and invasion in EC. The traditional endocrine treatment is ineffective in most ER negative and PR negative ECs, and even in some selleck chemical ER positive and PR positive ECs. In our investigation, 9 of the15 ER negative EC cases and 41 of the 61 ER positive EC cases were AR positive, and the majority of ECs were also FOXA1 positive.