Abstract
Abstract Tamoxifen is the most widely used endocrine therapy in estrogen receptor (ER)- positive breast cancer patients. Tamoxifen resistance has been a major clinical problem and is accountable for relapse in about one third of these patients. Most of these recurrent patients will inevitably receive chemotherapy. However, the association between tamoxifen-resistance and chemosensitivity in breast cancer has never been explored. We found that both mRNA and protein expression of BARD1 and BRCA1 were significantly upregulated in tamoxifen-resistant MCF7 and T47D breast cancer cell lines, when compared with their parental lines. Furthermore, the tamoxifen-resistant cells were markedly more resistant to DNA-damaging chemotherapy including cisplatin and doxorubicin, but not to paclitaxel. Silencing BARD1 or BRCA1 by siRNAs or inhibition of BRCA1 phosphorylation by Dinaciclib restored the sensitivity to cisplatin and doxorubicin in tamoxifen-resistant cells. In addition, we identified that activated PI3K/AKT/ERK pathway in tamoxifen-resistant cells was responsible for the upregulation of BARD1 and BRCA1. BKM120, a PI3K inhibitor, decreased the expression of BARD1 and BRCA1 in tamoxifen-resistant cells and re-sensitized them to cisplatin and doxorubicin both in vitro and in xenografted mice. More importantly, higher BARD1 expression was significantly associated with poorer prognosis in breast cancer patients. BARD1 and BRCA1 were also significantly upregulated in recurrent breast cancer samples after tamoxifen compared with their primary counterparts. These results indicate an important role of BARD1 and BRCA1 in the chemoresistance of ER-positive breast cancer. Targeting PI3K/Akt pathway or BRCA1 phosphorylation may help to overcome the resistance to DNA-damaging chemotherapy in these tumors. Citation Format: Liu Q, Zhu Y, Liu Y. Tamoxifen-resistant breast cancer cells are resistant to DNA-damaging chemotherapy because of upregulated BARD1 and BRCA1 [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-03-11.
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