Aberrant Claudin-6–Adhesion Signaling Promotes Endometrial Cancer Progression via Estrogen Receptor α

Abstract Cell adhesion proteins not only maintain tissue integrity, but also possess signaling abilities to organize diverse cellular events in a variety of physiologic and pathologic processes; however, the underlying mechanism remains obscure. Among cell adhesion molecules, the claudin (CLDN) family is often aberrantly expressed in various cancers, but the biological relevance and molecular basis for this observation have not yet been established. Here, we show that high CLDN6 expression accelerates cellular proliferation and migration in two distinct human endometrial cancer cell lines in vitro. Using a xenograft model, we also revealed that aberrant CLDN6 expression promotes tumor growth and invasion in endometrial cancer tissues. The second extracellular domain and Y196/200 of CLDN6 were required to recruit and activate Src-family kinases (SFK) and to stimulate malignant phenotypes. Knockout and overexpression of ESR1 in endometrial carcinoma cells showed that the CLDN6-adhesion signal links to estrogen receptor α (ERα) to advance tumor progression. In particular, aberrant CLDN6–ERα signaling contributed to collective cell behaviors in the leading front of endometrial cancer cells. Importantly, we demonstrate that CLDN6/SFK/PI3K-dependent AKT and SGK (serum- and glucocorticoid-regulated kinase) signaling in endometrial cancer cells targets Ser518 in the human ERα to activate ERα transcriptional activity in a ligand-independent manner, thereby promoting tumor progression. Furthermore, CLDN6, at least in part, also regulated gene expression in an ERα-independent manner. Implications: The identification of this machinery highlights regulation of the transcription factors by cell adhesion to advance tumor progression.