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141 Are Regulated by a FOXP3-KAT2B Axis and Associated Zhang et al. Breast Cancer Research (2017) 19:73 DOI 10.1186/s13058-017-0858-x RESEARCH ARTICLE Open Access MicroRNA-200c and microRNA- 141 are regulated by a FOXP3-KAT2B axis and associated with tumor metastasis in breast cancer Guangxin Zhang1,2, Wei Zhang3, Bingjin Li1, Erica Stringer-Reasor4, Chengjing Chu5, Liyan Sun3, Sejong Bae6, Dongquan Chen6, Shi Wei7, Kenneth Jiao8, Wei-Hsiung Yang9, Ranji Cui1*, Runhua Liu2,8* and Lizhong Wang2,8* Abstract Background: Members of the microRNA (miR)-200 family, which are involved in tumor metastasis, have potential as cancer biomarkers, but their regulatory mechanisms remain elusive. Methods: We investigated FOXP3-inducible breast cancer cells, Foxp3 heterozygous Scurfy mutant (Foxp3sf/+) female mice, and patients with breast cancer for characterization of the formation and regulation of the miR-200 family in breast cancer cells and circulation. Participants (259), including patients with breast cancer or benign breast tumors, members of breast cancer families, and healthy controls, were assessed for tumor and circulating levels of the miR-200 family. Results: First, we identified a FOXP3-KAT2B-miR-200c/141 axis in breast cancer cells. Second, aging Foxp3sf/+ female mice developed spontaneous breast cancers and lung metastases. Levels of miR-200c and miR-141 were lower in Foxp3sf/+ tumor cells than in normal breast epithelial cells, but plasma levels of miR-200c and miR-141 in the Foxp3sf/+ mice increased during tumor progression and metastasis. Third, in patients with breast cancer, the levels of miR-200c and 141 were lower in FOXP3low relative to those with FOXP3high breast cancer cells, especially in late-stage and metastatic cancer cells. The levels of miR-200c and miR-141 were higher in plasma from patients with metastatic breast cancer than in plasma from those with localized breast cancer, with benign breast tumors, with a family history of breast cancer, or from healthy controls. Finally, in Foxp3sf/+ mice, plasma miR-200c and miR-141 appeared to be released from tumor cells. Conclusions: miR-200c and miR-141 are regulated by a FOXP3-KAT2B axis in breast cancer cells, and circulating levels of miR-200c and miR-141 are potential biomarkers for early detection of breast cancer metastases. Keywords: microRNA, FOXP3, Breast cancer, Tumor metastasis, Circulation, Exosome Background identify individuals who are at high risk of metastases. In the USA, an estimated 231,840 women were diag- To reduce breast cancer metastasis-related morbidity nosed with breast cancer in 2015, and there were ap- and mortality, the ideal biomarker should be accessible proximately 40,290 deaths [1]. Within 3 years of for non-invasive sampling and sensitive enough to detect diagnosis, 10–15% of breast cancers develop distant me- early onset of tumor metastasis. To date, only a few tastases [2]. Therefore, predictive tests are needed to markers, such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor re- * Correspondence: [email protected]; [email protected]; [email protected] ceptor 2 (HER2), have been identified as predictors of 1Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun 130041, People’s Republic of China clinical responses to breast cancer treatments. None of 2Department of Genetics, University of Alabama at Birmingham, Birmingham, these markers, however, evaluate tumor invasion or pro- AL 35294, USA vide early detection of tumor metastasis. Full list of author information is available at the end of the article © The Author(s). 2017 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. Zhang et al. Breast Cancer Research (2017) 19:73 Page 2 of 13 MicroRNAs (miRs) are small non-coding RNA mole- mutation of Foxp3 (Foxp3sf/+), which causes a loss of cules that regulate gene expression. In breast cancers, ab- Foxp3 expression, frequently develop spontaneous breast errant miR expression influences tumor development and cancers (ER+, 14/18; PR+, 12/18; ErbB2+, 18/18) after 1 progression [3]. Some miRs are upregulated in breast can- year of age, and 40% of these mice with primary breast cer, whereas others are downregulated, suggesting that tumors also develop lung metastases [26]. Thus, this miRs may have tumor-specific profiles. MiRs are remark- mouse model is appropriate for finding and validating ably stable in the circulation, and in formalin-fixed, breast cancer biomarkers and for evaluating their cellu- paraffin-embedded tissues [4]. Thus, they have potential lar origin, identifying their mechanism of release, and to serve as breast cancer biomarkers. Circulating miRs, assessing the function of circulating miRs during tumor which are present in breast cancer patients, have potential progression and metastasis. In the present work, we ex- as biomarkers that can be obtained by a minimally inva- plored the relevance of FOXP3-mediated transcriptional sive procedure [5–10]. Members of the human and mouse regulation of miR-200 s in breast cancer cells in mice miR-200 family (miR-200 s), including two clusters (clus- and humans. We also investigated the cellular origin, ter 1: miR-200b, 200a, and 429, on chromosome 1, and mechanism of release, and function of plasma miR-200 s cluster 2: miR-200c and miR-141, on chromosome 12), in- in breast cancer cells and in mouse models. hibit the epithelial-mesenchymal transition (EMT) [11, 12] but promote the mesenchymal-epithelial transition (MET) Methods [13, 14], thereby regulating tumor metastasis by a reversible Cell lines, antibodies, and reagents EMT-MET transition. In cancer cells, miR-200 s induce Breast cancer cell lines MCF7, T47D, BT474, and MDA- epithelial differentiation by suppressing ZEB1/2 and subse- MB-468 were obtained from the American Type Culture quently increasing E-cadherin expression [11, 12]. Apart Collection (Manassas, VA, USA). Cell lines were authenti- from the miR-200-ZEB1/2-E-cadherin axis, miR-200 s in- cated by examination of morphology and growth character- hibit Wnt through CTNNB1,NOTCHthroughJAG1,and istics and were confirmed to be mycoplasma-free. A short SNAIL through SNAI2, and other direct targets, FN1, tandem-repeat analysis for DNA fingerprinting was also MSN, NTRK2, LEPR, and ARHGAP19,allofwhicharene- used to verify the human cell lines. Green fluorescent pro- cessary for tumor metastasis [15–17]. Decreased levels of tein (GFP) and FOXP3/GFP-Tet-off MCF7 cells were estab- miR-200 s in tumor cells have been implicated in the inva- lished and maintained in doxycycline (Dox, 10 μg/ml) as sion and metastasis of breast cancer [11, 12, 18], but, in described previously [25, 30]. Specific primary antibodies preclinical models, restoration of miR-200c reduced metas- were used to detect the following proteins: FOXP3 (ab450, tases [19], suggesting that the miR-200 s function as tumor 1:2,000, ABCAM, Cambridge, MA, USA), PCAF (KAT2B) suppressors. Conversely, some studies suggest that, in can- (C14G9, 1:1,000, Cell Signaling Technology, Danvers, MA, cer cells, miR-200 s promote tumor metastasis through USA), and PITX2 (ab98297, 1:2,000, ABCAM). The pEF1- promotion of tumor colonization at metastatic sites [13, FOXP3-V5 vector [31] or empty pEF1 vector was trans- 14]. In murine cancers and human xenograft models, miR- fected into cells using FuGENE6 (Promega, Madison, WI, 200-expressing tumor cells and extracellular vesicles from USA). KAT2B and PITX2 small interfering RNAs (siRNAs) these tumor cells promote breast cancer metastasis and are listed in Additional file 1: Table S1. confer the capacity for these cells to colonize distant tissues in an miR-200-dependent manner [20]. Further, high levels Experimental animals of circulating miR-200 s in breast cancer patients are asso- Mice with an sf mutation in the Foxp3 locus were pur- ciated with increased numbers of circulating tumor cells chased from the Jackson Laboratory (Bar Harbor, ME, (CTCs) [21], which are a predictor of metastasis up to 2 USA). The sf mouse has a spontaneous Foxp3 frameshift years prior to clinical diagnosis [22] and of shorter brain- mutation, resulting in loss of FOXP3 function. Homozy- metastasis-free survival [23]. Thus, circulating miR-200 s gous or hemizygous sf mice generally die within 2 weeks are promising biomarkers for breast cancer metastasis. after birth, but heterozygous scurfy female mice have a However, the cellular origin, mechanism of release, and normal life span. In our previous studies [26], we estab- function of circulating miR-200 s during tumor progression lished the Foxp3sf/+ mouse model, which was used here and metastasis remain elusive. for monitoring the mechanisms involved in the progres- FOXP3 functions as the master regulator in the devel- sion and metastasis of breast cancers. These mice have a opment and function of regulatory T cells [24]. Our BALB/c background. F1 Foxp3sf/+ female mice of appro- group found that FOXP3 is also a breast epithelial cell- priate genotypes were used. All animal experiments
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