In mice, the uterus undergoes dynamic changes regulated by estrogen and progesterone during the estrous cycle. Proper regulation of these changes is critical for successful pregnancy. The Family with sequence similarity 3 (Fam3) gene family, comprising Fam3a, Fam3b, Fam3c, and Fam3d, encodes cytokine-like proteins, but their uterine roles remain unclear. This study examined Fam3 expression in the mouse uterus across the estrous cycle and assessed estrogen-dependent regulation. RNA-seq analysis revealed increased Fam3b, Fam3c, and Fam3d expression during proestrus and estrus. Notably, Fam3d showed dynamic regulation, peaking in these stages. To test estrogen regulation, estradiol was administered to ovariectomized mice, showing maximal Fam3d expression at 24 h post-injection. ERα antagonist treatment blocked this induction, indicating ERα-mediated regulation. Immunofluorescence localized FAM3D to the cytoplasm of luminal and glandular epithelia, especially in the apical region, with no stromal or nuclear expression. These findings suggest that estrogen and Erα (Estrogen receptor alpha) signaling control Fam3d expression, implicating FAM3D in uterine epithelial function. This study provides novel insights into Fam3d’s role in uterine physiology and a foundation for exploring its function in reproduction.

The uterus is an important hormone-responsive tissue in the female reproductive system. Histologically, the uterus is comprised of three layers, including the perimetrium, myometrium, and endometrium. Among them, the endometrium has an essential function in embryo implantation and development to achieve successful gestation. It is the innermost layer of the uterus which consists of both luminal and glandular epithelial and stromal cells. In mammals, the uterine endometrium undergoes a dynamic cyclical growth and tissue remodeling controlled by the ovarian hormones, estrogen, and progesterone during the menstrual (human) and the estrous (rodent) cycle (Evans et al., 1990; Dharma et al., 2001; Wood et al., 2007). This dynamic remodeling involves the recurrent synchrony of cell proliferation, differentiation, and apoptosis, along with extracellular matrix (ECM) turnover, leukocyte infiltration, and angiogenesis (Evans et al., 1990). Estrogen is usually known to induce endometrium growth by thickening the mucosa during the follicular phase (Groothuis et al., 2007). On the other hand, progesterone blocks estrogen-induced endometrial growth and transforms it into a receptive state for blastocyst implantation. Classically, estrogen regulates the expression of an array of genes to mediate its major actions on uterine cells via its nuclear receptors, ERα and ERβ. On the other hand, progesterone regulates its actions on the uterine via progesterone receptor (PR), PR-A, and PR-B in the uterus (Mulac-Jericevic & Conneely, 2004).

The uterus is a dynamic organ in which the endometrium undergoes cyclic processes of proliferation, shedding, and regeneration under the influence of estrogen and progesterone. In particular, estrogen regulates the proliferation and differentiation of the endometrium and plays an important role in the development of gynecological diseases such as endometrial cancer. Farnesyl diphosphate synthase (FDPS) is a key enzyme involved in the mevalonate pathway, catalyzing the synthesis of farnesyl pyrophosphate (FPP), which plays an essential role in cholesterol biosynthesis and protein prenylation. In this study, we demonstrated using an in vivo mouse model that the expression of FDPS is regulated by estrogen. FDPS expression was specifically elevated during the proestrus stage of the estrous cycle and subsequently decreased. In ovariectomized (OVX) mice, FDPS expression was significantly increased 24 h after estrogen treatment, whereas this response was suppressed by treatment with the estrogen receptor alpha (ERα) antagonist, ICI 182,780. Although FDPS expression has been reported in various cancers, its role in endometrial cancer remains unclear. Histological and cellular analyses revealed that FDPS is highly expressed in human endometrial cancer tissues and in the endometrial cancer cell line Ishikawa, where it contributes to cell proliferation. These findings suggest that FDPS may play a role in the survival and growth of endometrial cancer cells. This study provides new insights into the potential function of FDPS in the uterus and suggests that targeting FDPS may represent a promising therapeutic strategy for endometrial cancer.