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

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Abstract

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.

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Abbreviations

AI:

Aromatase inhibitor

AKT/PKB:

Protein kinase B

ER:

Estrogen receptor

HER2:

Human epidermal growth factor receptor 2

MAPK:

Mitogen-activated protein kinase

MTT:

3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazolium bromide

PDCD4:

Programmed cell death 4

PI3K:

Phosphatidylinositol 3′-kinase

PTEN:

Phosphatase and tensin homolog

SiRNA:

Short interfering RNA

TCGA:

The cancer genome atlas

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Acknowledgments

The study was supported by the National Institutes of Health (R01 ES08258 to SC). Research reported in this publication included work performed at the Bioinformatics Core supported by the National Cancer Institute of the National Institutes of Health under award number P30CA33572.

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The authors declare that there is no conflict of interest.

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Authors and Affiliations

  1. Department of Cancer Biology, Beckman Research Institute, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA, 91010, United States

    Zhike Chen, Yuanzhong Wang, Hei Jason Chan & Shiuan Chen

  2. Bioinformatics Core, Department of Molecular Medicine, Beckman Research Institute, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA, 91010, United States

    Yate-Ching Yuan & Zheng Liu

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  1. Zhike Chen
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  2. Yate-Ching Yuan
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Correspondence to Shiuan Chen.

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Chen, Z., Yuan, YC., Wang, Y. et al. Down-regulation of programmed cell death 4 (PDCD4) is associated with aromatase inhibitor resistance and a poor prognosis in estrogen receptor-positive breast cancer. Breast Cancer Res Treat 152, 29–39 (2015). https://doi.org/10.1007/s10549-015-3446-8

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