Effects of Jaeumkanghwa-tang on tamoxifen responsiveness in preclinical ER+ breast cancer model.

Resistance to endocrine therapy remains a clinical challenge in the treatment of estrogen receptor positive (ER+) breast cancer. We investigated if adding a traditional Asian herbal mixture consisting of 12 herbs, called Jaeumkanghwa-tang (JEKHT), to tamoxifen (TAM) therapy might prevent resistance and recurrence in the ER+ breast cancer model of 7,12-dimethylbenz[a]anthracene (DMBA)-exposed Sprague Dawley rats. Rats were divided into four groups treated as follows: 15 mg/kg TAM administered via diet as TAM citrate (TAM only); 500 mg/kg JEKHT administered via drinking water (JEKHT only group); TAM + JEKHT; and no treatment control group. The study was replicated using two different batches of JEKHT. In both studies, a significantly higher proportion of ER+ mammary tumors responded to TAM if animals also were treated with JEKHT. The risk of local recurrence also was reduced. JEKHT alone was mostly ineffective. In addition, JEKHT prevented development of premalignant endometrial lesions in TAM treated rats. Co-treatment of antiestrogen resistant LCC9 human breast cancer cells with 1.6 mg/ml JEKHT reversed their TAM resistance in dose response studies in vitro. Several traditional herbal medicine preparations can exhibit anti-inflammatory properties and may increase antitumor immune activities in the tumor microenvironment. In the tumors of rats treated with both JEKHT and TAM, expression of Il-6, Foxp3/T regulatory cell (Treg) marker, and Tgfβ1 that activates Tregs were significantly downregulated compared with TAM only group. These findings indicate that JEKHT may prevent TAM-induced evasion of tumor immune responses.