title: Down-regulation of programmed cell death 4 (PDCD4) is associated with aromatase inhibitor resistance and a poor prognosis in estrogen receptor-positive breast cancer.
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.
authors.affiliation: Department of Cancer Biology, Beckman Research Institute, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA, 91010, United States.
authors.forename: Zhike
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Bioinformatics Core, Department of Molecular Medicine, Beckman Research Institute, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA, 91010, United States.
authors.forename: Yate-Ching
authors.initials: YC
authors.lastname: Yuan
authors.affiliation: Department of Cancer Biology, Beckman Research Institute, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA, 91010, United States.
authors.forename: Yuanzhong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Bioinformatics Core, Department of Molecular Medicine, Beckman Research Institute, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA, 91010, United States.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Cancer Biology, Beckman Research Institute, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA, 91010, United States.
authors.forename: Hei Jason
authors.initials: HJ
authors.lastname: Chan
authors.affiliation: Department of Cancer Biology, Beckman Research Institute, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA, 91010, United States. schen@coh.org.
authors.forename: Shiuan
authors.initials: S
authors.lastname: Chen
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D047072:Aromatase Inhibitors / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D045744:Cell Line, Tumor; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D035683:MicroRNAs / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018931:Antineoplastic Agents, Hormonal; D051017:Apoptosis Regulatory Proteins; D047072:Aromatase Inhibitors; D035683:MicroRNAs; D020928:Mitogen-Activated Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D016601:RNA-Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; C524940:MIRN21 microRNA, human; C114487:PDCD4 protein, human