Cyclins and their cyclin-dependent kinases are critical regulators of cell-cycle progression. Previous work has demonstrated that CCNA2 is a regulator of steroid hormonal signaling (5). CCNA2 has been shown to regulate the transcriptional activity of ESR1 and act as a coregulator of PGR (6–8). Aljubran et al. (4) analyzed the expression of CCNA2 in endometrial biopsies from patients undergoing in vitro fertilization prior to the procedure, during the proliferative and secretory phases of the menstrual cycle. Patients that achieved a successful pregnancy had higher levels of CCNA2 in endometrial stromal cells. Further, endometrial stromal cells from patients with higher CCNA2 showed higher levels of ESR1 and PGR expression and increased cell proliferation. These results indicate a relationship between CCNA2 levels and the ability of endometrial stromal cells to proliferate and prepare the uterus for pregnancy in response to steroid hormone stimulation. However, the relationship among ESR1, PGR, and CCNA2 was correlative and needed further experimentation to decipher the mechanism between CCNA2 and nuclear receptor signaling in the regulation of endometrial stromal cell proliferation and the ability of the uterus to support pregnancy.

The authors examined the effects of CCNA2 deficiency to further determine the role of CCNA2 in pregnancy. They evaluated the ability of the uterus to support pregnancy and examined steroid regulation in uterine function. In a PGRCre mouse model, uterine-specific ablation of Ccna2 resulted in infertility. The mice were able to ovulate, produce pregnancy hormones, and support attachment and implantation of embryos. However, the postimplantation survival of the embryos was impaired, resulting in embryo resorption due to the embryo’s inability to develop a functional placenta. Analysis of this phenotype demonstrated that ablation of Ccna2 caused a hypoplastic uterus with an impaired response of the uterus to estrogen stimulation. The inability of the endometrial stromal cells to respond to estrogen resulted in the selective impairment of ESR1-regulated genes. The major ESR1 target was PGR, which showed decreased expression that resulted in an altered decidual response. The authors also used an siRNA approach to knock down CCNA2 in human endometrial stromal cells. There was a similar dependence on ESR1 regulation of PGR in the transformed cells. CCNA2 expression in human endometrial stromal cells decreased with decidualization, and CCNA2 knockdown in these cells decreased PGR expression and the ability of the cells to undergo hormonal-induced decidualization. These in vivo and in vitro results demonstrate that CCNA2 is critical for priming the endometrial stromal cells for the hormonal induction of decidualization (Figure 1).

CCNA2 supports embryo implantation and embryo development. In stromal cells, CCNA2 regulates ESR1 activity, which controls PGR expression. The action of CCNA2, ESR1, and PGR results in stromal cell proliferation and their differentiation into epithelioid decidual cells. Subsequent PGR expression in decidual cells allows appropriate implantation and placentation of the embryo.