An ovarian cancer model with positive ER: Reversion of ER antagonist resistance by Src blockade

Approximately 60% of ovarian cancers are positive for the estrogen receptor (ER); however, ER-targeted treatment is disappointing due to drug resistance as compared with breast cancer. In estrogen-sensitive cancers, estrogen activates Src to phosphorylate p27 promoting its degradation and increasing cell cycle progression. Since Src is frequently activated in ovarian cancers, we investigated whether combined Src and ER blockade by saracatinib and fulvestrant would circumvent anti-estrogen resistance. In 20 out of 40 enrolled patients with immunohistochemically ER-positive ovarian cancer, phosphorylated Src (p-Src) at the site of 416 tyrosine was expressed with a propensity for metastasis and a poorer disease-free survival (DFS) at 3 years following ER antagonist treatment. The effects of ER and Src blockade on cell cycle were assayed in estrogen receptor alpha (ER alpha)-positive ovarian cancer. We observed that Src activity was fairly greater in anti-estrogen-resistant ovarian cancer cells than that in the anti-estrogen-sensitive cell line. Estrogen activated Src via ER-Src binding and ER translocation from cytoplasm to nucleus. Mitogenesis was mediated via ER alpha, not ER beta. Combined saracatinib and fulvestrant increased p27 and inhibited cell cycle progression. Furthermore, dual therapy induced autophagy and inhibited ovarian cancer xenograft growth more effectively than monotherapy. Saracatinib facilitated the therapeutic effects of fulvestrant by antagonizing the estrogen-mediated Src activation. These are supportive of further preclinical assessment of combined fulvestrant and saracatinib in patients with ovarian cancer.