Rapamycin enhances the sensitivity of ER‑positive breast cancer cells to tamoxifen by upregulating p73 expression

Zhu,Lei; Li,Xiao‑Xia; Shi,Liang; Wu,Jing; Qian,Jia‑Yi; Xia,Tian‑Song; Zhou,Wen‑Bin; Sun,Xi; Zhou,Xu‑Jie; Wei,Ji‑Fu; Ding,Qiang

doi:10.3892/or.2018.6842

Rapamycin enhances the sensitivity of ER‑positive breast cancer cells to tamoxifen by upregulating p73 expression

Authors:
- Lei Zhu
- Xiao‑Xia Li
- Liang Shi
- Jing Wu
- Jia‑Yi Qian
- Tian‑Song Xia
- Wen‑Bin Zhou
- Xi Sun
- Xu‑Jie Zhou
- Ji‑Fu Wei
- Qiang Ding
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Affiliations: Jiangsu Breast Disease Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China, Department of Critical Care Medicine, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China, Research Division of Clinical Pharmacology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
Published online on: November 1, 2018 https://doi.org/10.3892/or.2018.6842
Pages: 455-464

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Abstract

A total of 70% of breast cancers express the estrogen receptor (ER)α; therefore, targeting the ER may be an effective endocrine therapy with which to inhibit breast cancer growth. Tamoxifen is the most common‑used clinically used drug for the treatment of advanced or metastatic ER‑positive (ER+) breast cancer. However, a substantial proportion of patients become resistant to endocrine therapies. To overcome this limitation, in this stud, we sought to maximize the benefits associated with tamoxifen therapy via drug combination strategies. We demonstrated that rapamycin, an FDA‑approved mammalian target of rapamycin (mTOR) inhibitor, enhanced the effects of endocrine therapy with tamoxifen, and the concentration of tamoxifen required for ER+ breast cancer cell growth inhibition was substantially reduced. Moreover, treatment with rapamycin plus tamoxifen significantly inhibited tumor growth in vivo. In addition, this synergistic effect may be mediated by the induction of p73. We revealed a novel mechanism in which p73 increases ERα expression by directly binding to the promoter region of the ERα gene. Taken together, the findings of this study indicate that combination therapy with rapamycin and tamoxifen underlying p73‑mediated ERα expression may provide new insight into the drug combination for the treatment of ER+ breast cancer.

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