Inhibitory effects of aromatase inhibitor on estrogen receptor-alpha positive ovarian cancer in mice

Background: Estrogen causes proliferation of ovarian cancer cells. Although hormone therapy with an antiestrogen agent is an optional therapy for recurrent epithelial ovarian cancers, both basic and clinical researches are insufficient. We here examine the efficacy of an aromatase inhibitor (AI) for peritonitis carcinomatosa, the late stage of ovarian cancer. Methods: Estrogen receptor (ER)alpha was assayed in four ovarian cancer cell lines by the RT-PCR method. Using ovariectomized nude mice, peritonitis carcinomatosa consisting of OVCAR-3 cells with the strongest ER alpha expression or DISS cells with weaker ER alpha expression was prepared. The survival period was compared between the letrozole group (5 mg/kg/day orally; n = 10) and the control group (n = 10). In addition, the degree of angiogenesis and occurrence of apoptosis were compared using tumor tissue from the abdominal cavity. The expression of aromatase and the protein involving in ER alpha signaling were examined in tumors immunohistochemically. Results: Survival period in OVCAR-3 tumors was significantly prolonged in the letrozole group, compared with the control group (P < 0.05), whereas that in DISS tumors was not different between the both groups. The microvessel density in tumors and expression of VEGF decreased significantly in the letrozole group compared to the control group. The incidence of apoptosis did not differ significantly between these groups. No adverse event was observed accompanying the administration of letrozole. The expressions of aromatase, ER alpha and FOXP1 that is associated with ER alpha signaling were reduced in tumors by letrozole administration. Conclusions: Letrozole was effective for ovarian cancers with abundant expression of ER alpha. Inhibition of angiogenesis and of ascites production appeared to contribute to prolongation of the survival period.