ERalpha36, a variant of estrogen receptor-alpha, acts as a dominant-negative factor in both estrogen-dependent and estrogenindependent transactivation signaling pathways, and is a key factor in the promotion, progression and prognosis of breast cancers. Caveolin-1, a 22- to 24-kD integral membrane protein, may function as a tumor suppressor in inhibiting of many growth-promoting signaling pathways. It was shown that downregulation of Caveolin-1 strengthens the interaction of ERalpha and Caveolin-1. In conclusion, Caveolin-1 gene silencing activated the PI3K/AKT signaling pathway in an ERalpha36-dependent way. Our finding may provide a promising therapeutic target of breast cancer.