Abstract
Tamoxifen(TAM) is one of the most effective endocrine treatment for estrogen receptor(ER)-positive breast cancer, however drug resistance greatly limits benefit of it. Our purpose is to uncover the role of Beclin 1 in tamoxifen resistance and prognosis of ER positive breast cancer. We established a tamoxifen resistant ER-positive breast cancer cell subline MCF-7R presenting with higher Beclin 1 and human epidermal growth factor receptor 2(HER2) levels than MCF-7. Silencing Beclin 1 decreased levels of HER2 and significantly promoted TAM sensitivity of MCF-7 and MCF-7R in vitro. Overexpression of HER2 could reverse TAM sensitivity, which was formerly increased in Beclin 1 downregulated cell. Beclin 1 level was not only positively correlated with level of HER2 but also negatively correlated with overall survival of ER-positive breast cancer patients. Using bioinformatic methods, Beclin 1 mRNA was found to be negatively correlated with overall survival in breast cancer patients receiving TAM treatment. This study indicated for the first time that lower HER2 expression by Beclin 1 downregulation contributes to alteration of tamoxifen sensitivity and low Beclin 1 predicts favorable outcome in ER-positive breast cancer.
Highlights
Breast cancer is the most frequent and the second death cause of cancer among females [1] and approximately 70% human breast cancers are estrogen receptor(ER)-positive [2]
We observed that the mRNA and protein levels of Beclin 1 in MCF-7R cells were increased compared to parental MCF-7 cells
Expression of Beclin 1 mRNA showed > 1.6 fold higher and Beclin 1 protein showed >1.3 fold higher in MCF-7R cells compared to MCF-7 cells (Figure 1B, 1C)
Summary
Breast cancer is the most frequent and the second death cause of cancer among females [1] and approximately 70% human breast cancers are estrogen receptor(ER)-positive [2]. Endocrine drugs are still the key treatment for ER-positive breast cancer patients preoperatively, post-operatively, or during the metastatic disease stage. Endocrine drugs function by reducing estrogen levels or blocking ER signaling, which including selective estrogen receptor modulators (SERMs), selective estrogen receptor down-regulators (SERDs), and aromatase inhibitors (AIs) etc. Tamoxifen(TAM), as one of the SERMs, is the most frequently used endocrine drug which can competitively block ER to inhibit estrogen signaling and tumor growth [3]. A recent meta-analysis reported that 5 years of adjuvant TAM reduced 15-year risks of breast cancer recurrence and death from the data of 21,457 patients [4]. De novo and acquired resistance which occur in about 30% of the patients, seriously hinder the benefit of TAM [5, 6, 7]
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