Down-regulation of programmed cell death 4 (PDCD4) is associated with aromatase inhibitor resistance and a poor prognosis in estrogen receptor-positive breast cancer

被引：65

作者：

Chen, Zhike ^{[1
]}

Yuan, Yate-Ching ^{[2
]}

Wang, Yuanzhong ^{[1
]}

Liu, Zheng ^{[2
]}

Chan, Hei Jason ^{[1
]}

Chen, Shiuan ^{[1
]}

机构：

[1] City Hope Natl Med Ctr, Beckman Res Inst, Dept Canc Biol, Duarte, CA 91010 USA

[2] City Hope Natl Med Ctr, Beckman Res Inst, Dept Mol Med, Bioinformat Core, Duarte, CA 91010 USA

来源：

BREAST CANCER RESEARCH AND TREATMENT | 2015年 / 152卷 / 01期

基金：

美国国家卫生研究院;

关键词：

PDCD4; Aromatase inhibitor; HER2; miR-21; Breast cancer; Prognosis; TUMOR-SUPPRESSOR GENE; ENDOCRINE RESISTANCE; EUKARYOTIC TRANSLATION; SIGNAL-TRANSDUCTION; PROTEIN-KINASE; EXPRESSION; MICRORNA-21; TRANSFORMATION; ACTIVATION; MIR-21;

D O I：

10.1007/s10549-015-3446-8

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

Progression or recurrence due to resistance to aromatase inhibitors (AIs) is a significant clinical problem for a considerable number of patients with breast cancer. Programmed cell death 4 (PDCD4), a tumor suppressor protein, is targeted for degradation during tumor progression. In the current study, we aimed to examine PDCD4 expression and regulation in AI-resistant breast cancer cells, and its association with survival in patients with estrogen receptor (ER)-positive breast cancer. We determined PDCD4 expression levels in AI-resistant breast cancer cell lines and ER-positive breast cancer tumors, investigated the regulation of PDCD4 in AI-resistant breast cancer cell lines, and carried out a Kaplan-Meier survival analysis in two independent cohorts that included a total of 420 patients with ER-positive breast cancer. We found that PDCD4 expression was down-regulated in AI-resistant breast cancer cells, and this down-regulation was inversely correlated with activation of HER2 signaling. Moreover, lower expression of PDCD4 was significantly associated with HER2 positive status in ER-positive breast tumors. Down-regulation of PDCD4 was mediated through up-regulation of HER2 via the mitogen-activated protein kinase (MAPK), protein kinase B (PKB/AKT), and miR-21 in AI-resistant breast cancer cells. MiR-21 inhibitor and the ER down-regulator fulvestrant induced PDCD4 expression and decreased cell proliferation in AI-resistant breast cancer cells. Furthermore, forced overexpression of PDCD4 resensitized AI-resistant cells to AI or hormone deprivation. Finally, we identified that down-regulation of PDCD4 was associated with a lower rate of disease-free survival in patients with ER-positive breast cancer and high histologic grade of breast tumors. In summary, our study shows that expression of PDCD4 is down-regulated by HER2 signaling in AI-resistant breast cancer. Down-regulation of PDCD4 is associated with AI resistance and a poor prognosis in patients with ER-positive breast cancer.

引用

页码：29 / 39

页数：11

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