Breast cancer is the most common type of cancer in women worldwide. More than 70% of breast cancers are estrogen receptor alpha (ERα) positive, indicating that they might be treatable with endocrine therapy. However, half of patients with ERα-positive breast cancer develop endocrine resistance, a major roadblock to successful therapy. In a new study, researchers sought to learn more about ERα-positive breast cancer to support the development of better treatments. The enzyme TRIM3, a regulator of protein stability vs. breakdown, was upregulated in ERα-positive breast cancer tissues, and high TRIM3 expression was associated with poor survival in patients receiving endocrine therapy. In experiments on mice and cell lines, TRIM3 promoted ERα signaling and was required for cancer growth and migration. Specifically, the filamin/NHL domain of TRIM3 bound to the DNA-binding domain of ERα in the nucleus. This association stabilized ERα, preventing its degradation, possibly by facilitating a protein-labeling process called K63-linked polyubiquitination. Although additional research is needed, the findings identify TRIM3 as a novel modulator of ERα signaling, suggesting that TRIM3 is a potential treatment target for the most common type of breast cancer.