Abstract
Tamoxifen resistance is accountable for relapse in many ER-positive breast cancer patients. Most of these recurrent patients receive chemotherapy, but their chemosensitivity is unknown. Here, we report that tamoxifen-resistant breast cancer cells express significantly more BARD1 and BRCA1, leading to resistance to DNA-damaging chemotherapy including cisplatin and adriamycin, but not to paclitaxel. Silencing BARD1 or BRCA1 expression or inhibition of BRCA1 phosphorylation by Dinaciclib restores the sensitivity to cisplatin in tamoxifen-resistant cells. Furthermore, we show that activated PI3K/AKT pathway is responsible for the upregulation of BARD1 and BRCA1. PI3K inhibitors decrease the expression of BARD1 and BRCA1 in tamoxifen-resistant cells and re-sensitize them to cisplatin both in vitro and in vivo. Higher BARD1 and BRCA1 expression is associated with worse prognosis of early breast cancer patients, especially the ones that received radiotherapy, indicating the potential use of PI3K inhibitors to reverse chemoresistance and radioresistance in ER-positive breast cancer patients.
Highlights
Tamoxifen resistance is accountable for relapse in many estrogen receptor (ER)-positive breast cancer patients
We show that tamoxifen-resistant breast cancer cells are resistant to DNA-damaging chemotherapy because of upregulated BARD1 and BRCA1, which is caused by activated PI3K/AKT pathway
We found that higher expression of BARD1 was associated with decreased overall survival (OS) in ER-positive breast cancer patients from publicly available Curtis breast cancer data set[22] published on oncomine platform (Fig. 1c) and in the metaanalysis of breast cancer patients from 27 data sets, many of which do not provide the details of ER positivity (Supplementary Fig. 2a). qPCR and western blot confirmed that the mRNA and protein levels of BARD1 in MCF7 tamoxifen-resistant cell line (MCF7-Re) cells were significantly higher than those in MCF-Pa cells (Fig. 1d)
Summary
Tamoxifen resistance is accountable for relapse in many ER-positive breast cancer patients. We report that tamoxifen-resistant breast cancer cells express significantly more BARD1 and BRCA1, leading to resistance to DNA-damaging chemotherapy including cisplatin and adriamycin, but not to paclitaxel. For recurrent ER-positive and Her2-positive breast cancers, anti-Her[2] therapy plus chemotherapy is generally the favorable treatment It has never been reported whether prior endocrine resistance could affect the response to chemotherapy in these patients. We show that tamoxifen-resistant breast cancer cells are resistant to DNA-damaging chemotherapy because of upregulated BARD1 and BRCA1, which is caused by activated PI3K/AKT pathway. Our results indicate an important role of BARD1/BRCA1 in chemoresistance of ER-positive breast cancer patients
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