Dihydrotanshinone I: A Target for STAT3 in the Therapy of Tamoxifen‐Resistant Breast Cancer

Abstract

Breast cancer is the most prevalent tumour in women. Over two-thirds of breast cancers are estrogen receptor (ER)-positive breast cancers. These breast cancer patients are prone to tamoxifen resistance during breast cancer treatment. There is still a lack of effective clinical treatment for tamoxifen-resistant breast cancer. Dihydrotanshinone I (DHTS) promotes various types of apoptosis in tumour cells. Our network pharmacology study revealed that DHTS has a strong binding capacity to STAT3. Tamoxifen-resistant breast cancers are often accompanied by STAT3 activation. However, there are no reports of DHTS for tamoxifen-resistant breast cancer. Subsequent in vitro experiments also confirmed that DHTS promoted apoptosis in MCF-7-TamR cells, down-regulated the performance of STAT3, pSTAT3, and BCL-2, and activated the production of apoptosisassociated PARP1 and cleaved caspase3. This process could be rescued by overexpression of BCL-2 downstream of STAT3 and was not rescued by either the cytokine EGF or the cytokine PDGF, which promote STAT3 phosphorylation. We hypothesized that DHTS targeting STAT3 promotes apoptosis in MCF-7-TamR cells, mainly by affecting STAT3 phosphorylation. Our research approach described above may provide new ideas for the treatment of tamoxifen-resistant breast cancer.