Down-regulation of programmed cell death 4 (PDCD4) is associated with aromatase inhibitor resistance and a poor prognosis in estrogen receptor-positive breast cancer
Open accessAbstract
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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Loss of PDCD4 expression is correlated with poor prognosis and survival in breast cancer, colorectal cancer, lung cancer, ovarian cancer, and renal cell carcinoma.
“the loss of PDCD4 expression is correlated with poor prognosis and survival in breast cancer [89], colorectal cancer [90], lung cancer [17], ovarian cancer [91] and renal cell carcinoma [92] (Table 2).”
From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [89]
Citation [89] is attached to the breast-cancer portion of the sentence, not the other cancers listed. Section 3.6 reports that low PDCD4 expression was associated with poorer disease-free survival in two cohorts of patients with ER-positive breast cancer. The claim omits that population and outcome restriction; page numbers are not available in the supplied copy. (LLM, conf=0.84)
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- Authors
- Chen, Z., Yuan, Y.-C., Wang, Y., Liu, Z., Chan, H. J., & Chen, S.
- Affiliations
- City Of Hope National Medical Center (US)
- Corresponding author
- Chen, Shiuan
- Venue
- Breast Cancer Research and Treatment
- Published
- 2015-05-31
- Volume
- 152
- Issue
- 1
- Pages
- 29-39
- ISSN
- 0167-6806 (ISSN-L)
- 1573-7217
- PMC
- PMC4470793
- OpenAlex
- W1885174764
- Cited by
- 59
- References
- 56
- Citations by year
- 2026: 1 · 2025: 3 · 2023: 3 · 2022: 5 · 2021: 8 · 2020: 2 · 2019: 11 · 2018: 11 · 2017: 5 · 2016: 8 · 2015: 2
- FWCI
- 5.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Breast Cancer Research and Treatment (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (R01 ES08258)
- National Cancer Institute (P30CA33572)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Advanced Breast Cancer Therapies
- Keywords
- PDCD4, aromatase inhibitor resistance, estrogen receptor-positive breast cancer, HER2 signaling, miR-21, MAPK signaling, Akt signaling, fulvestrant, disease-free survival, prognosis, histologic grade, hormone deprivation
- MeSH terms
- Breast Neoplasms, Female, Humans, Prognosis, Receptors, Estrogen, Signal Transduction, Down-Regulation, Gene Expression Regulation, Neoplastic, RNA-Binding Proteins, Erb-b2 Receptor Tyrosine Kinases, Receptor, ErbB-2, Antineoplastic Agents, Hormonal, Drug Resistance, Neoplasm, Mitogen-Activated Protein Kinases, MicroRNAs, Cell Line, Tumor, Aromatase Inhibitors, Apoptosis Regulatory Proteins, Proto-Oncogene Proteins c-akt, Kaplan-Meier Estimate
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