Abstract:Background
Since the human papillomavirus vaccines do not eliminate preexisting infections, nonsurgical alternative approaches to cervical intraepithelial neoplasia (CIN) have been required. We previously reported that FOXP4 (forkhead box transcription factor P4) promoted proliferation and inhibited squamous differentiation of CIN1‐derived W12 cells. Since it was reported that FOXP expressions were regulated by the androgen/androgen receptor (AR) complex and AR was expressed on the CIN lesions, in this study w… Show more
“…Recently, we reported that forkhead box transcription factor P4 (FOXP4) is associated with the androgen/AR pathway in cervical intraepithelial neoplasia cells 15 . FOXP4 was expressed in human cell lines of ECC, HEC50B, HEC108, and HEC265 (Supplementary Fig.…”
Section: Resultsmentioning
confidence: 99%
“…The empty vector (pCAGIPuro) and a human AR overexpression vector were described in a previous paper 15 . The protein-coding sequences of human and mouse FOXP4 to subclone into the pCAGIPuro vector were amplified by PCR using primers (Supplementary Table 4 ).…”
Although low estrogen is considered to suppress uterine endometrial carcinoma, the most cases occur in the postmenopausal stage. After menopause, the production of androgen level also declines. Therefore, to resolve the above enigma, we hypothesize that the postmenopausal decline of androgen is a trigger of its progression. In the present study, to validate this hypothesis, we examine the pathological roles of androgen/AR by analyzing clinical data, culturing endometrioid cancer cell lines, and using murine models. Clinical data show that androgen receptor (AR) expression and serum dihydrotestosterone (DHT) are associated with lower disease-free survival (DFS). DHT suppresses malignant behaviors in AR-transfected human endometrial cancer cells (ECC). In ovariectomized Ptenff/PRcre/+ mice, DHT decreases the proliferation of spontaneously developed murine ECC. In AR-transfected human ECC and Ptenff/PRcre/+ mice, DHT suppresses FOXP4 expression. FOXP4-overexpressed human ECC increases, while FOXP4-knocked-down ECC shows decreased malignant behaviors. DHT/AR-mediated ECC suppression is restored by FOXP4 overexpression. The high FOXP4 expression is significantly correlated with low postoperative DFS. These findings indicate that the androgen/AR system suppresses the malignant activity of endometrial carcinoma and that downstream FOXP4 is another target molecule. These findings will also impact developments in clinical approaches to elderly health.
“…Recently, we reported that forkhead box transcription factor P4 (FOXP4) is associated with the androgen/AR pathway in cervical intraepithelial neoplasia cells 15 . FOXP4 was expressed in human cell lines of ECC, HEC50B, HEC108, and HEC265 (Supplementary Fig.…”
Section: Resultsmentioning
confidence: 99%
“…The empty vector (pCAGIPuro) and a human AR overexpression vector were described in a previous paper 15 . The protein-coding sequences of human and mouse FOXP4 to subclone into the pCAGIPuro vector were amplified by PCR using primers (Supplementary Table 4 ).…”
Although low estrogen is considered to suppress uterine endometrial carcinoma, the most cases occur in the postmenopausal stage. After menopause, the production of androgen level also declines. Therefore, to resolve the above enigma, we hypothesize that the postmenopausal decline of androgen is a trigger of its progression. In the present study, to validate this hypothesis, we examine the pathological roles of androgen/AR by analyzing clinical data, culturing endometrioid cancer cell lines, and using murine models. Clinical data show that androgen receptor (AR) expression and serum dihydrotestosterone (DHT) are associated with lower disease-free survival (DFS). DHT suppresses malignant behaviors in AR-transfected human endometrial cancer cells (ECC). In ovariectomized Ptenff/PRcre/+ mice, DHT decreases the proliferation of spontaneously developed murine ECC. In AR-transfected human ECC and Ptenff/PRcre/+ mice, DHT suppresses FOXP4 expression. FOXP4-overexpressed human ECC increases, while FOXP4-knocked-down ECC shows decreased malignant behaviors. DHT/AR-mediated ECC suppression is restored by FOXP4 overexpression. The high FOXP4 expression is significantly correlated with low postoperative DFS. These findings indicate that the androgen/AR system suppresses the malignant activity of endometrial carcinoma and that downstream FOXP4 is another target molecule. These findings will also impact developments in clinical approaches to elderly health.
“…It has been shown that androgens promote squamous differentiation of atypical cells in cervical intraepithelial neoplasia through an ELF3-dependent pathway ( Figure 3 ). 10 Figure 3 Role of androgens/AR in cervical FOXP4-related proliferation and squamous differentiation DHT/AR inhibits the functional regulation of FOXP4 (a nuclear transcription factor) and NOTCH3 (a differentiation-related gene) in cervical epithelial cells, promoting cell squamous differentiation and suppressing proliferation, thus promoting the progression of CIN from grade 1 to grade 3. …”
“…Recently, androgen has been reported to be a new factor regulating squamous differentiation involved in the early progression of cervical intraepithelial neoplasia (CIN), suggesting a novel nonsurgical hormone-induced differentiation therapy could be used against CIN1 and CIN2 [ 35 ].…”
Advanced and recurrent gynecological cancers lack effective treatment and have poor prognosis. Besides, there is urgent need for conservative treatment for fertility protection of young patients. Therefore, continued efforts are needed to further define underlying therapeutic targets and explore novel targeted strategies. Considerable advancements have been made with new insights into molecular mechanisms on cancer progression and breakthroughs in novel treatment strategies. Herein, we review the research that holds unique novelty and potential translational power to alter the current landscape of gynecological cancers and improve effective treatments. We outline the advent of promising therapies with their targeted biomolecules, including hormone receptor-targeted agents, inhibitors targeting epigenetic regulators, antiangiogenic agents, inhibitors of abnormal signaling pathways, poly (ADP-ribose) polymerase (PARP) inhibitors, agents targeting immune-suppressive regulators, and repurposed existing drugs. We particularly highlight clinical evidence and trace the ongoing clinical trials to investigate the translational value. Taken together, we conduct a thorough review on emerging agents for gynecological cancer treatment and further discuss their potential challenges and future opportunities.
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