AFF3 upregulation mediates tamoxifen resistance in breast cancers.

Abstract

BACKGROUND:

Although tamoxifen is a highly effective drug for treating estrogen receptor-positive (ER+) breast cancer, nearly all patients with metastasis with initially responsive tumors eventually relapse, and die from acquired drug resistance. Unfortunately, few molecular mediators of tamoxifen resistance have been described. Here, we describe AFF3 (AF4/FMR2 family member 3), which encodes a nuclear protein with transactivation potential that confers tamoxifen resistance and enables estrogen-independent growth.

METHODS:

We investigated AFF3 expression in breast cancer cells and in clinical breast cancer specimens with western blot and Real-time PCR. We also examined the effects of AFF3 knockdown and overexpression on breast cancer cells using luciferase, tetrazolium, colony formation, and anchorage-independent growth assays in vitro and with nude mouse xenografting in vivo.

RESULTS:

AFF3 was overexpressed in tamoxifen-resistant tumors. AFF3 overexpression in breast cancer cells resulted in tamoxifen resistance, whereas RNA interference-mediated gene knockdown reversed this phenotype. Furthermore, AFF3 upregulation led to estrogen-independent growth in the xenograft assays. Mechanistic investigations revealed that AFF3 overexpression activated the ER signaling pathway and transcriptionally upregulated a subset of ER-regulated genes. Clinical analysis showed that increased AFF3 expression in ER+ breast tumors was associated with worse overall survival.

CONCLUSIONS:

These studies establish AFF3 as a key mediator of estrogen-independent growth and tamoxifen resistance and as a potential novel diagnostic and therapeutic target.

• Authors: Yawei Shi, Yang Zhao, Yunjian Zhang, NiJiati AiErken, Nan Shao, Runyi Ye, Ying Lin, Shenming Wang
• Journal: Journal of experimental & clinical cancer research : CR (J Exp Clin Cancer Res) Vol. 37 Issue 1 Pg. 254 (Oct 16 2018) ISSN: 1756-9966 [Electronic] England
• PMID: 30326937 (Publication Type: Journal Article)

Chemical References

• AFF3 protein, human
• Antineoplastic Agents, Hormonal
• Nuclear Proteins
• Tamoxifen

Topics

• Animals
• Antineoplastic Agents, Hormonal (pharmacology)
• Breast Neoplasms (drug therapy, genetics, pathology)
• Drug Resistance, Neoplasm
• Female
• Heterografts
• Humans
• Mice
• Nuclear Proteins (biosynthesis, genetics, metabolism)
• Signal Transduction
• Tamoxifen (pharmacology)
• Up-Regulation