Estrogen signaling drives breast cancers but reduces colorectal cancer incidence. Accumulating evidence support that activation of ERbeta (ESR2) can prevent colon cancer development, and this receptor is thus a potential target for receptor-selective preventive therapy. Furthermore, unlike in most cancers, ERbeta is highly expressed in granulosa cell tumors (GCTs), a rare subtype of ovarian tumors. Its function in the development of this type of cancer is still unknown, and we are exploring its basic function in mice, including comparison with knockout mice. Data support regulation of tumor suppressors and oncogenes, anti-inflammatory activity, and impact on microbiota. However, the underlying mechanism is not fully understood.