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AFF3 Upregulation Mediates Tamoxifen Resistance in Breast

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AFF3 Upregulation Mediates Tamoxifen Resistance in Breast Shi et al. Journal of Experimental & Clinical Cancer Research (2018) 37:254 https://doi.org/10.1186/s13046-018-0928-7 RESEARCH Open Access AFF3 upregulation mediates tamoxifen resistance in breast cancers Yawei Shi1†, Yang Zhao2†, Yunjian Zhang1, NiJiati AiErken3, Nan Shao1, Runyi Ye1, Ying Lin1* and Shenming Wang1* 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. Keywords: AFF3, Breast cancer, Estrogen receptor-positive, Tamoxifen, Resistance Background malignancies [3]. The treatment options for such tumors Breast cancer is one of the three most frequently diagnosed include targeted anti-hormonal drugs, of which tamoxifen malignancy and the second-leading cause of cancer-related has been the first choice for decades, both in the adjuvant death in women. Every year, an estimated 1 million new and the recurrent setting [4]. However, approximately 50% cases were diagnosed worldwide [1]. Breast cancer can be of patients with metastatic disease fail to respond, and divided into subtypes according to histopathological fea- practically all patients with metastasis with initially respon- tures such as progesterone receptor (PR), estrogen receptor sive tumors eventually develop acquired resistance, which (ER), or erb-b2 receptor tyrosine kinase 2 (ERBB2 or becomes the cause of death [5, 6]. It has been demon- HER2) status, and include ER-positive, HER2-positive, or strated that nuclear hormone receptor co-regulator differ- triple-negative breast cancer [2]. ER-positive (ER+) breast ential expression [7, 8], growth factor signaling crosstalk cancer constitutes around two-thirds of all breast [9–12], cyclin-dependent kinases (CDKs) [13], CDK inhibi- tors [14, 15], microRNA regulation [16], and in recent * Correspondence: [email protected]; [email protected] years, acquired ER somatic mutations and alterations [17– † Yawei Shi and Yang Zhao contributed equally to this work. 19], mediate tamoxifen resistance. Although the causes of 1The Department of Breast and Thyroid surgery, the First Affiliated Hospital of Sun Yat-sen University, 58# Zhongshan Two Road, Guangzhou 510080, tamoxifen resistance vary, the most predominant mecha- Guangdong, China nisms are poorly understood. Further insight into the Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Shi et al. Journal of Experimental & Clinical Cancer Research (2018) 37:254 Page 2 of 10 molecular mediators of tamoxifen and hormone therapy obtained from the American Type Culture Collection, and resistance would greatly impact the ability to target genes growninDMEMsupplementedwith10%fetalbovine and pathways that could surmount drug resistance, and serum (FBS), within a humidified atmosphere containing ameliorate clinical outcomes. 5% CO2 at 37 °C. AFF3 (AF4/FMR2 family member 3, or LAF4) was first considered a lymphoid-specific gene; it is expressed and Establishment of resistant cell lines locate in the nuclear of B cells [20]. However, AFF3 Parental MCF7 and T47D cells were continuously − mRNA is nearly imperceptible or in most cases com- treated with tamoxifen (Tam, 10 7 M, > 6 months), and pletely absent in plasma cells and many other tissues the resistant derivatives (TamRes) were selected when [20]. AFF3 encodes a 1227–amino acid protein that is the initially sensitive cells resumed comparable growth presumed to play a role in transcriptional regulation, as to the parental cells. it can directly bind to DNA and contains at least two domains with transactivation activity. These evidence in- Tissue specimens dicated that AFF3 may be a lymphoid lineage restricted Fresh human tissue samples including 10 breast cancer gene with regulated function. AFF3 shares high sequence tissues and 3 normal mammary tissues were collected identity with the member of AF4/FMR2 family member, from the First Affiliated Hospital of Sun Yat-sen Univer- such as AFF1 (AF4/FMR2 family member 1, or AF4), sity, and were snap frozen and stored at liquid nitrogen AFF2 (AF4/FMR2 family member 2, or FMR2) and until use. A cohort of 101 paraffin-embedded, archived AFF4 (AF4/FMR2 family member 4, or MCEF)[21–23]. breast cancer specimens was used to determine the The AFF1 gene has been mapped to chromosome 4 and clinical significance AFF3, these specimens were clinically is the target of t(4;11) translocation that occurs in ap- diagnosed as breast cancer at from 2000 to 2008. The de- proximately 50% of acute lymphoblastic leukemia (ALL) tail information was shown in Additional file 1: Table S1. cases in children aged < 1 year [24, 25], and results in For the use of all specimens for research purposes, prior fusion with the MLL gene [26]. MLL and AFF4 fusion patient’s written informed consents and approval from the also occurs in infant ALL but at a much lower First Affiliated Hospital of Sun Yat-sen University. frequency. AFF3 and MLL fusion was observed in three independent cases of infant ALL of late [27–29]. Two RNA extraction and real-time quantitative PCR cases resulted from t(2;11) translocations [27, 28], and Total cellular RNA was extracted using the TRIzol solution the remaining case was due to ins(11,2) insertion [29]. (Invitrogen), according to the manufacturer’sprotocol.Re- These gene re-arrangement retained the transactivation verse transcription and Real-time PCR were performed domain of AFF3, and AFF1 and AFF4, suggesting that using RT Real-Time™ SYBR Green (Bio-Rad Laboratories, deregulated expression of the downstream target genes Berkeley, CA, USA). The housekeeping gene GAPDH was is a common mechanism through which the fusion pro- used as internal controls for mRNAs, respectively. The teins contribute to oncogenesis. Interestingly, AFF3 is primers used were as follows: AFF3 forward: 5′- ACTC also deregulated in breast tumors [30]. However, its role AACAGGATGATGGC -3′, AFF3 reverse: 5′- TGCCTAA in the development of breast cancer and the molecular AGTGTTCTGGATC -3′; GAPDH forward: 5′-GACTCAT mechanism underlying its involvement in tumorigenesis GACCACAGTCCATGC-3′, GAPDH reverse: 3′-AGAGG remain ambiguous. CAGGGATGATGTTCTG-5′. In this study, we show that AFF3 is overexpressed in ER+ human breast cancers, leading to tamoxifen resistance Western blotting and estrogen-independent growth, and that patients with Cellular proteins were prepared in sample buffer primary breast cancers with AFF3 overexpression have [62.5 mM Tris-HCl (pH 6.8), 10% glycerol, 2% SDS] and worse survival. Our study identifies AFF3 as a new medi- heated for 10 min at 100 °C. Equal quantities of protein ator of ER signaling and tamoxifen resistance with poten- were electrophoresed through a 10% SDS/polyacrylamide tial clinical implications. gel and transferred to a PVDF membrane (Millipore, Billerica, MA, USA). The membranes were incubated with Methods anti-AFF3 and anti-GAPDH antibodies (1:1,000; Cell Cell culture Signaling Technology, Danvers, MA, USA), respectively. Primary normal breast epithelial cell line, MCF-10A, were purchased from the American Type Culture Collection Oligonucleotides, siRNA, plasmids, retroviral infection and (ATCC, Manassas, VA, USA) and cultured according to transfection the manufacturer’s instruction. Breast cancer cell lines in- For depletion of AFF3, siRNAs were synthesized and cluding BT549, HCC1937, MDA-MB231, MDA-MB468, purified by RiboBio (The AFF3 siRNAs sequence were MDA-MB361, T47D, MCF-7 and
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