Loss of cables is associated with development of endometrial hyperplasia and cancer

Abstract

Background: Cables is a cell cycle regulatory protein and tumor suppressor(1,2). Cables can interact with cyclin dependent kinases (cdk)(2,3) and it appears to modulate cdk activity by enhancing cdk phosphorylation. Loss of Cables has been associated with the development of squamous cancers of the head and neck(4) and colon(4), ovarian(5) and endometrial cancer (EC)(1). Furthermore, there is a coordinate loss of Cables associated with endometrial hyperplasia suggesting that Cables my play an early role in the transformation of the endometrium. The functional importance of Cables was only recently realized in the Cables mutant mouse which developed endometrial hyperplasia and following exposure to chronic estrogen developed endometrial adenocarcinoma(1). These results combined with the finding that Cables expression is elevated during the progesterone dominant secretory phase of the menstrual cycle would suggest that loss of Cables may serve to promote type 1 endometrial cancer(6,7). It is not known, however, if Cables is lost in the high-grade endometrioid, serous and/or clear cell cancers. High-grade endometrioid, serous and/or clear cell endometrial cancer (EC) are often referred to as type 2 EC(6,7). In addition, it is not known whether Cables inhibits cell proliferation in EC cell lines and/or whether its expression in well-differentiated and poorly differentiated EC cells is hormonally regulated. Objective: Experiments were conducted to address whether Cables is lost in high-grade EC, its expression is hormonally regulated and whether it had the potential to inhibit proliferation in well-differentiated and/or poorly differentiated EC cells in vitro and in vivo. Results: Cables expression is lost in the high-grade endometrioid, serous and clear cell carcinoma similar to what is observed in low-grade endometrioid cancer with greater than 80% showing either complete or partial Cables loss. Treatment with progesterone increased cables expression in well-differentiated EC cells (Ishikawa) whereas it had no effect on cables expression in poorly differentiated EC cells (SK-UT2). The progesterone-induced increase in cables was abrogated in the presence of a progesterone receptor (PR) antagonist, suggesting the PR mediates the increase through the classical nuclear receptor. Immunocompromised mice which hosted well-differentiated EC cells overexpressing Cables had little to no evidence of tumor whereas the majority of the animals which hosted the parent cell line developed excessive tumor burden. Conclusions: Collectively these results suggest that Cables is an important regulator of cell proliferation and an early loss of Cables expression may contribute to the development of EC.