Benzophenone Modulates GPER/ERα–PI3K/mTOR Signaling and Induces Epigenetic Alterations in Ovarian Small Cell Carcinoma of Hypercalcemic Type

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and highly aggressive ovarian malignancy with poorly understood environmental modifiers. Although benzophenone (BP) is a widely used environmental chemical with reported estrogenic activity, its effects on SCCOHT remain unknown. Here, we investigated whether BP alters malignant phenotypes and signaling and epigenetic programs in COV434 cells, a SCCOHT‐derived cell line. Cells were exposed to BP (1, 10, or 100 μM), and estrogen receptor signaling, proliferation, migration, clonogenicity, and three‐dimensional spheroid invasion were evaluated together with transcriptional and epigenetic changes. BP‐induced ERα nuclear translocation to a level comparable with estradiol and enhanced proliferation, migration, colony formation, and spheroid invasion. These phenotypic changes were accompanied by increased expression of genes involved in GPER/ERα/PI3K/mTOR signaling and in cell cycle progression, metastasis, and angiogenesis. BP also increased DNMT1, DNMT3A , and DNMT3B expression, elevated H3K27me3 and H3K36me3, and was associated with increased HOXA9 methylation. Together, these findings show that BP can elicit estrogen‐like responses and promote aggressive phenotypes in SCCOHT cells, accompanied by alterations in oncogenic signaling and epigenetic remodeling. More broadly, this study highlights the need to further examine whether environmental exposure to endocrine‐disrupting chemicals can influence SCCOHT progression.