Endometrial cancer is the most common form of uterine cancer and is most frequently diagnosed in women over 55. A new study proposes a key mechanism that promotes the formation of endometrial tumors. It starts with ERα, one of two receptors activated by the sex hormone estrogen. Experiments on human cancer cells showed that activating ERα significantly increased the expression of the protein PIWIL1, which is detected in different forms of cancer in both men and women. A closer look revealed that ERα binds to a unique site of the PIWIL1 gene known as a half-ERE. That binding signals the expression of the PIWIL1 protein and thereby promotes tumor growth. Understanding how this estrogen-stimulated pathway works in the female body could help researchers and clinicians expand treatment options available to women with endometrial cancer.