Supplementary Figure from Transcription Factor FOSL1 Enhances Drug Resistance of Breast Cancer through DUSP7-Mediated Dephosphorylation of PEA15

Retraction of ‘Long non-coding RNA PVT1 facilitates cell proliferation by epigenetically regulating FOXF1 in breast cancer’ by Guangcheng Guo et al., RSC Adv., 2018, 8, 2740–2750, https://doi.org/10.1039/C7RA12042G.

Background Breast cancer (BC) threatens the health of women around the world. Researchers have proved that hsa_circ_0005505 (circ_IRAK3) facilitates BC cell invasion and migration, but the regulatory mechanisms of circ_IRAK3 in BC remain mostly unknown. We aim to explore a new mechanism by which circ_IRAK3 promotes BC progression. Methods Levels of circ_IRAK3, microRNA (miR)-603, and kinesin family member 2A (KIF2A) mRNA in BC tissues and cells were examined by quantitative real-time polymerase chain reaction (qRT-PCR). The cell cycle progression, colony formation, and proliferation of BC cells were evaluated by flow cytometry, plate clone, or 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assays. The migration, invasion, and apoptosis of BC cells were determined by transwell or flow cytometry assays. Several protein levels were detected using western blotting. The targeting relationship between circ_IRAK3 or KIF2A and miR-603 was verified via dual-luciferase reporter assay. The role of circ_IRAK3 in vivo was verified by xenograft assay. Results We observed higher levels of circ_IRAK3 in BC tissues and cell lines than their respective controls. Functional experiments presented that circ_IRAK3 silencing induced BC cell apoptosis, curbed cell proliferation, migration, and invasion in vitro, and decreased tumor growth in vivo. Mechanistically, circ_IRAK3 could modulate kinesin family member 2A (KIF2A) expression through acting as a microRNA (miR)-603 sponge. miR-603 silencing impaired the effects of circ_IRAK3 inhibition on the malignant behaviors of BC cells. Also, the repressive effects of miR-603 mimic on the malignant behaviors of BC cells were weakened by KIF2A overexpression. Conclusions circ_IRAK3 exerted a promoting effect on BC progression by modulating the miR-603/KIF2A axis, providing a piece of novel evidence for circ_IRAK3 as a therapeutic target for BC.

Abstract Breast cancer is one of the commonest malignancies in women with first occurrence and fifth mortality in the world. However, drug resistance has always been a major obstacle to cancer treatment. Transcription factors have been reported to have close association with drug resistance of tumors. Recently, by analyzing the data from Gene Expression Omnibus database (GSE76540), we found that transcription factor FOS like 1, AP-1 transcription factor subunit (FOSL1) was significantly upregulated in the transcriptome of doxorubicin-resistant breast cancer cells compared with that in sensitive parental cells. Therefore, we aim to explore the regulatory mechanism of FOSL1 in affecting the drug resistance of breast cancer cells. FOSL1 expression in doxorubicin-resistant breast cancer cells was firstly examined through qRT-PCR, and then its influence on the drug resistance of breast cancer cells was explored through a series of in vitro and in vivo mechanism assays. Results showed that FOSL1 promoted the drug resistance of breast cancer cells to doxorubicin both in intro and in vivo. It positively regulated the transcription of dual specificity phosphatase 7 (DUSP7) in breast cancer doxorubicin-resistant cells and DUSP7 also enhanced the drug resistance of breast cancer cells. Furthermore, FOSL1 promoted the dephosphorylation of proliferation and apoptosis adaptor protein 15 (PEA15) through DUSP7. In conclusion, it was verified that FOSL1 promoted the drug resistance in breast cancer through DUSP7-mediated dephosphorylation of PEA15. Implications: These initial findings suggest that the FOSL1/DUSP7/PEA15 pathway may provide a theoretical guidance for breast cancer treatment.

Poor response of tumors to radiotherapy is a major clinical obstacle. Because of the dynamic characteristics of the epigenome, identification of possible epigenetic modifiers may be beneficial to confer radio-sensitivity. This research was set to examine the modulation of ectodermal-neural cortex 1 (ENC1) in radio-resistance in breast carcinoma (BC). In silico identification and immunohistochemical staining revealed that overexpression of ENC1 promoted BC metastasis to the bone and brain. Moreover, its overexpression promoted the translocation of YAP1/TAZ into the nucleus and enhanced expression of GLI1, CTGF, and FGF1 through the Hippo pathway. ENC1 expression was controlled by a ~10-kb long SE. ENC1-SEdistal deletion reduced ENC1 expression and inhibited the malignant behavior of BC cells and their resistance to radiotherapy. The binding sites on the ENC1-SE region enriched the shared sequence between TCF4 and ENC1 promoter. Knocking-down TCF4 inhibited luciferase activity and H3K27ac-enriched binding of the ENC1-SE region. Additionally, SE-driven ENC1 overexpression mediated by TCF4 may have clinical implications in radio-resistance in BC patients. Our findings indicated that ENC1 overexpression is mediated by SE and the downstream TCF4 to potentiate the Hippo/YAP1/TAZ pathway. Targeting this axis might be a therapeutic strategy for overcoming BC radio-resistance.

An increasing amount of evidence has proven the vital role of circular RNAs (circRNAs) in cancer progression. However, there remains a dearth of knowledge on the function of circRNAs in triple-negative breast cancer (TNBC). Utilizing a circRNA microarray dataset, four circRNAs were identified to be abnormally expressed in TNBC. Among them, circBACH2 was most significantly elevated in TNBC cancerous tissues and its high expression was positively correlated to the malignant progression of TNBC patients. In normal human mammary gland cell line, the overexpression of circBACH2 facilitated epithelial to mesenchymal transition and cell proliferation. In TNBC cell lines, circBACH2 knockdown suppressed the malignant progression of TNBC cells. Mechanistically, circBACH2 sponged miR-186-5p and miR-548c-3p, thus releasing the C-X-C chemokine receptor type 4 (CXCR4) expression. The interference of miR-186-5p/miR-548c-3p efficiently promoted the cell proliferation, migration, and invasion suppressed by circBACH2 knockdown in the TNBC cell lines. Finally, circBACH2 knockdown repressed the growth and lung metastasis of TNBC xenografts in nude mice. In summary, circBACH2 functions as an oncogenic circRNA in TNBC through a novel miR-186-5p/miR-548c-3p/CXCR4 axis.

Development of the acquired resistance is one major obstacle during chemotherapy for cancer patients. Exosomes mediate intercellular communication and cause environmental changes in tumor progression by transmitting active molecules. In this study, the role of long noncoding RNA H19 within exosomes is elucidated in terms of regulating doxorubicin (DOX) resistance of breast cancer. As a result, increased H19 expression was observed in DOX-resistant breast cancer cells in comparison with the corresponding parental cells. Suppression of H19 significantly lowered DOX resistance by decreasing cell viability, lowering colony-forming ability, and inducing apoptosis. Moreover, extracellular H19 could be moved to sensitive cells via being incorporated into exosomes. Treating sensitive cells with exosomes from resistant cells increased the chemoresistance of DOX, while downregulation of H19 in sensitive cells abated this effect. Taken together, H19 could be delivered by exosomes to sensitive cells, leading to the dissemination of DOX resistance. Our finding highlights the potential of exosomal H19 as a molecular target to reduce DOX resistance.

Background: Beast cancer is the most common women cancer worldwide, while two third of them are ER alpha positive breast cancer. Among the ER alpha positive breast cancer, about 80% are P53 wild type, indicating the potential tumor suppression role in ER alpha positive breast cancer. Since P53 is an important safeguard to inhibit cell malignant transformation, reactivating P53 signaling could a plausible approach to treat breast cancer. Methods: TRIM3 protein levels were measured by western blot, while the P53 classical target genes were measured by real-time PCR. WST1 assay were used to measure cell proliferation, while cleaved caspase-3 was used to detect cell apoptosis. Protein stability and ubiquitin assay were used to detect the P53 protein ubiquitin and stability. The immuno-precipitation assays were used to detect the protein interactions. Immuno-staining was used to detect the protein localization of P53 and TRIM3, while the ubiquitin-based immuno-precipitation assays were used to detect the specific ubiquitination manner of P53. Results: In our study, we identified TRIM3 as an endogenous inhibitor for P53 signaling. TRIM3 depletion inhibited breast cancer cell proliferation and promoted apoptosis. In addition, TRIM3 depletion increased P53 protein level in breast cancer cell. Further investigation showed that TRIM3 could associate with P53 and promote P53 K48-linked ubiquitination and degradation. Conclusion: Our study identified a novel post-translational modification mechanism between TRIM3 and P53. TRIM3 depletion or blockage could be a promising strategy to rescue P53 signaling and inhibit breast cancer progression.

目的 PS2,E-Cad癌变组织表达与中晚期乳腺癌治疗效果及预后的相关性探究.方法 收集来我院就诊的乳腺癌患者86例,均为随访5年以上的患者.采用免疫组织化学的方法,对上述乳腺癌患者癌变组织的石蜡包埋切片中的PS2,E-Cad表达水平进行检测,分析PS2,E-Cad表达水平与影响乳腺癌治疗及预后因素(肿瘤大小、TNM分期、组织学分级、淋巴结转移情况)的相关性.结果 86例乳腺癌患者的癌变组织中PS2、E-Cad的表达与乳腺癌患者的治疗效果、肿瘤大小、TNM分期、组织学分级、淋巴结转移情况等方面均存在明显的相关性,E-Cad与PS2的表达阳性率在SD与PD患者间存在差异,SD患者的阳性率明显高于PD患者,差异有统计学意义(P<0.05);肿瘤大小≤2cm患者的E-Cad与PS2的表达阳性率明显高于肿瘤大小>2cm的患者,差异有统计学意义(P<0.05);TNM分期为Ⅱ期患者的E-Cad与PS2表达阳性率明显高于Ⅲ、Ⅳ期患者,差异有统计学意义(P<0.05);组织学分期Ⅱ期患者的E-Cad与PS2表达阳性率明显高于Ⅲ期患者,差异有统计学意义(P<0.05);发生淋巴结转移患者的E-Cad与PS2表达阳性率明显低于未发生转移的患者,差异有统计学意义(P<0.05).结论 E-Cad、PS2在癌组织中的表达与乳腺癌的进程密切相关,对E-Cad、PS2的表达进行检测可以有助于判断乳腺癌的治疗及预后情况,为乳腺癌的临床治疗提供重要的理论依据.

Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China Background: Baicalin is a natural compound from the roots of Scutellaria lateriflora Georgi, which plays anti-cancer role in multiple cancers. However, the exact role and potential underlying mechanism of baicalin in breast cancer (BC) remain poorly understood. Methods: Thirty BC patients were recruited in this study. MCF-10A,MCF-7 andMDA-MB-231 cells were used to investigate the anti-cancer role of baicalin in vitro. Cell viability, migration, invasion and apoptosis were measured by MTT, trans-well and flow cytometry, respectively. The expression levels of microRNA-338-3p (miR-338-3p) and microrchidia family CW-type zincfinger 4 (MORC4) were measured by quantitative real-time polymerase chain reaction or Western blot. The interaction between miR-338-3p and MORC4 was explored by luciferase reporter assay and RNA immunoprecipitation. Results: We found that Baicalin treatment inhibited cell viability, migration and invasion but promoted apoptosis of BC cells. The expression of miR-338-3p was decreased in BC tissues and cells and miR-338-3p overexpression suppressed cell viability, migration and invasion but induced apoptosis. MiR-338-3p expression was reversed by baicalin exposure and inhibition of miR-338-3p attenuated the role of baicalin in viability, apoptosis, migration and invasion. MORC4 mRNA level was increased in BC tissues and cells, which was decreased by baicalin exposure. MORC4 was a target of miR-338-3p and its overexpression alleviated the effect of miR-338-3p on cell viability, apoptosis, migration and invasion. Conclusion: In conclusion, baicalin suppressed cell viability, migration and invasion but promoted apoptosis in BC cells by regulating miR-338-3p and MORC4, indicating the promising pharmacological value of baicalin in BC treatment.

Background Baicalin is a natural compound from the roots of Scutellaria lateriflora Georgi, which plays anti-cancer role in multiple cancers. However, the exact role and potential underlying mechanism of baicalin in breast cancer (BC) remain poorly understood. Methods Thirty BC patients were recruited in this study. MCF-10A, MCF-7 and MDA-MB-231 cells were used to investigate the anti-cancer role of baicalin in vitro. Cell viability, migration, invasion and apoptosis were measured by MTT, trans-well and flow cytometry, respectively. The expression levels of microRNA-338-3p (miR-338-3p) and microrchidia family CW-type zinc-finger 4 (MORC4) were measured by quantitative real-time polymerase chain reaction or Western blot. The interaction between miR-338-3p and MORC4 was explored by luciferase reporter assay and RNA immunoprecipitation. Results We found that Baicalin treatment inhibited cell viability, migration and invasion but promoted apoptosis of BC cells. The expression of miR-338-3p was decreased in BC tissues and cells and miR-338-3p overexpression suppressed cell viability, migration and invasion but induced apoptosis. MiR-338-3p expression was reversed by baicalin exposure and inhibition of miR-338-3p attenuated the role of baicalin in viability, apoptosis, migration and invasion. MORC4 mRNA level was increased in BC tissues and cells, which was decreased by baicalin exposure. MORC4 was a target of miR-338-3p and its overexpression alleviated the effect of miR-338-3p on cell viability, apoptosis, migration and invasion. Conclusion In conclusion, baicalin suppressed cell viability, migration and invasion but promoted apoptosis in BC cells by regulating miR-338-3p and MORC4, indicating the promising pharmacological value of baicalin in BC treatment.

Long non-coding RNA gastric carcinoma high-expressed transcript 1 (lncRNA GHET1) is highly expressed in many tumors. The aim of the present study was to determine whether GHET1 inhibition decreases growth and metastasis of MCF-7 breast cancer cells by modulating epidermal growth factor receptor (EGFR) expression. In vitro, lncRNA GHET1 knockdown suppressed cell proliferation, migration, and invasion and enhanced cell apoptosis by maintaining MCF-7 cells in the G1 phase of the cell cycle. Furthermore, lncRNA GHET1 knockdown reduced the expression of EGFR and related proteins. Treatment of mice with a GHET1 inhibitor prevented tumor growth in vivo. The results indicate that lncRNA GHET1 inhibition directly suppresses EGFR expression, significantly inhibiting the downstream PI3K/AKT/Cyclin D1/MMP2/9 pathway. This mechanism may underlie the suppression of breast cancer cell activities including proliferation, migration, and invasion. In conclusion, lncRNA GHET1 knockdown suppresses tumor growth and metastasis by suppressing the activity of EGFR and downstream pathways.

目的 研究消结安胶囊联合枸橼酸他莫昔芬片治疗乳腺增生症的临床研究.方法 选取2015年12月-2017年12月郑州大学第一附属医院接收的乳腺增生患者100例为研究对象,将所有患者随机分为对照组和治疗组,每组各50例.对照组口服枸橼酸他莫昔芬片,1片/次,2次/d.治疗组在对照组治疗的基础上口服消结安胶囊,2粒/次,3次/d.两组患者均持续治疗2个月.观察两组的临床疗效,比较两组的乳腺超声指标和雌激素水平.结果 治疗后,对照组和治疗组的总有效率分别为82.00%、95.00%,两组比较差异有统计学意义(P<0.05).治疗后,两组乳腺腺体层厚度、肿块直径、输乳管内径和低回声区直径均显著降低,同组治疗前后比较差异有统计学意义(P<0.05);且治疗组这些乳腺超声指标明显低于对照组,两组比较差异具有统计学意义(P<0.05).治疗后,两组雌二醇、催乳素水平显著降低,孕酮水平显著升高,同组治疗前后比较差异有统计学意义(P<0.05);且治疗组这些雌激素水平明显优于对照组,两组比较差异具有统计学意义(P<0.05).结论 消结安胶囊联合枸橼酸他莫昔芬片治疗乳腺增生症具有较好的临床疗效,能够改善患者乳腺超声指标和雌激素水平,安全性较好,具有一定临床推广应用价值.

目的 观察多西他赛联合卡培他滨治疗对蒽环类耐药晚期乳腺癌的临床疗效及不良反应.方法 38例蒽环类耐药晚期乳腺癌患者采用多西他赛联合卡培他滨治疗.结果 全组38例患者共完成189周期治疗,均可评价疗效,其中CR 2例(5.3％)、PR 20例(52.6％)、SD 7例(18.4％)、PD 9例(23.7％),总有效率为57.9％.主要不良反应为粒细胞减少、手足综合征、恶心呕吐、腹泻、脱发、口腔炎等.结论 多西他赛联合卡培他滨治疗蒽环类耐药晚期乳腺癌有较好的疗效,且不良反应可以耐受.

Aims: Some studies suggested that TOX high mobility group box family member 3 (TOX3) rs3803662 polymorphism was associated with the risk of breast cancer. However, the results were controversy. Therefore, in order to derive a more comprehensive estimation of the association between TOX3 rs3803662 polymorphism and breast cancer risk, we conducted a meta-analysis to investigate this relationship. Materials and Methods: An electronic literature search was conducted using the following database: PubMed, EMBASE, and China National Knowledge Infrastructure till to March 31, 2015. The strength of the associations between the TOX3 rs3803662 polymorphism and breast cancer risk in per alle model was measured by odds ratios (ORs) and 95% confidence intervals (CIs). Results: A statistically significant association between TOX3 rs3803662 polymorphism and breast cancer risk was fond. The data showed that TOX3 rs3803662 polymorphism could increase the risk of breast cancer (OR = 1.20; 95% CI: 1.16-1.25; P < 0.00001). In the subgroup analysis of race, Caucasians, Asians, and Hispanics also showed increased breast cancer risk (OR = 1.21; 95% CI: 1.17-1.25; P < 0.00001; OR = 1.20; 95% CI: 1.08-1.33; P = 0.0004; OR = 1.32; 95% CI: 1.12-1.57; P = 0.001). However, African-Americans with TOX3 rs3803662 polymorphism showed decreased breast cancer risk (OR = 0.95; 95% CI: 0.86-1.04; P = 0.28), although the result was not significant. When considered estrogen receptor (ER) status, we found that ER+ subjects and ER-subjects all had increased breast cancer risk, if they carried this polymorphism (OR = 1.27; 95% CI: 1.19-1.35; P < 0.00001; OR = 1.12; 95% CI: 1.08-1.17; P < 0.00001). Similarly, both progesterone receptor-positive (PR+) subjects and PR- subjects all showed increased breast cancer risk, if they carried this polymorphism (OR = 1.32; 95% CI: 1.17-1.49; P < 0.00001; OR = 1.15; 95% CI: 1.09-1.23; P < 0.00001). Conclusions: This meta-analysis suggested that TOX3 rs3803662 polymorphism was associated with increased breast cancer risk.

Objective To explore the effect of low intensity of porphyrin mediated photodynamic therapy (PDT) on the radiosensitization in cholangiocarcinoma cells and its related mechanisms.Methods 2,7-Dichlorodi-hydrofluorescein diacetate (DCFH-DA) probe was used to detect the intracellular reactive oxygen species (ROS) production;Cell viability was evaluated by cell counting kit-8 (CCK-8) assays.Flow cytometry was used to quantify the apoptotic level of cells;Clonogenic survival assay was performed to assess the radiosensitizing effect of the radiosensitizer;Apoptosis related proteins were detected by Western blotting.Results Low intensity of PDT does not lead to death of QBC939 cells,whereas provides an elevated ROS environment in the mitochondria.The increasing intracellular level of ROS is demonstrated to enhance the radiosensitivity of QBC939 cells with a supra-additive synergistic effect of "0 + 1 ＞ 1 ".The apoptotic rates in the PDT + radiotherapy group and the radiotherapy alone group were (15.45 ± 1.23) ％ and (6.35 ± 0.84) ％ respectively (P =0.001).In addition,the low intensity of PDT achieves a high SER10 value of 1.59,which is much larger than that of the most popularly used radiosensitizers,cisplatin (1.27),and paclitaxel (1.32).The expression of phosphorylated RAC-alpha serine/threonine-protein kinase (p-Akt) and phosphorylated extracellular regulated protein kinases (p-ERK) proteins decreased more significant after PDT + radiotherapy when compared to the radiotherapy alone (p-AKT and p-ERK were declined by (53.6 ± 14.2) ％ and (49.8 ± 17.5) ％,respectively).Conclusion Low intensity of PDT is an ideal method for radiotherapy sensitization and has great potential for clinical application.

miR-30d has been shown to play pivotal roles in cancer development, and has the potential to act as a diagnostic biomarker and therapeutic target in breast cancer. However, the specific function and molecular mechanism of miR-30d in breast cancer cell growth and metastasis is still unknown. The present study seeks to shed light on the potential contribution of the MiR-30d-KLF-11-STAT3 pathway in breast cancer. The results revealed that miR-30d levels were markedly increased in the breast cancer cell lines BT474, MDA-MB-231, HCC197, and MDA-MB-468 compared with the non-tumor mammary gland MCF10A cell line. Furthermore, the miR-30d mimic increased BT474 and MDA-MB-231 breast cancer cell survival, inhibited apoptosis and increased Bcl-2 expression, whilst inhibited Bax protein levels. miR-30d mimics promote BT474 and MDA-MB-231 cell migration, invasion, and mediate the EMT phenotype. However, miR-30d inhibitors reverse all of the effects of miR-30d mimics on breast cancer cell biology. Also, we observed that KLF-11 is a direct target of miR-30d and KLF-11 and pSTAT3 expression are determined by miR-30d. Finally, the results suggest that miR-30d plays essential roles in breast cancer cells in a manner that is dependent on the levels of KLF-1 and pSTAT3. In summary, miR-30d appears to be a novel diagnostic biomarker and treatment target in breast cancer.

BACKGROUND:Breast cancer has been the first death cause of cancer in women all over the world. Metastasis is believed to be the most important process for treating breast cancer. There is evidence that lncRNA MEG3 functions as a tumor suppressor in breast cancer metastasis. However, upstream regulation of MEG3 in breast cancer remain elusive. Therefore, it is critical to elucidate the underlying mechanism upstream MEG3 to regulate breast cancer metastasis.METHODS:We employed RT-qPCR and Western blot to examine expression level of miR-506, DNMT1, SP1, SP3 and MEG3. Besides, methylation-specific PCR was used to determine the methylation level of MEG3 promoter. Wound healing assay and transwell invasion assay were utilized to measure migration and invasion ability of breast cancer cells, respectively.RESULTS:SP was upregulated while miR-506 and MEG3 were downregulated in breast tumor tissue compared to adjacent normal breast tissues. In addition, we found that miR-506 regulated DNMT1 expression in an SP1/SP3-dependent manner, which reduced methylation level of MEG3 promoter and upregulated MEG3 expression. SP3 knockdown or miR-506 mimic suppressed migration and invasion of MCF-7 and MDA-MB-231 cells whereas overexpression of SP3 compromised miR-506-inhibited migration and invasion.CONCLUSIONS:Our data reveal a novel axis of miR-506/SP3/SP1/DNMT1/MEG3 in regulating migration and invasion of breast cancer cell lines, which provide rationales for developing effective therapies to treating metastatic breast cancers.

Background: plasmacytoma variant translocation 1 (PVT1) has been identified as an oncogenic long non-coding RNA (lncRNA) in multiple cancers including breast cancer. However, its molecular basis has not been exhaustively elucidated. Methods: RT-qPCR assay was used to detect PVT1 expression in tissues and cells. The effect of PVT1 and FOXF1 on breast cancer cell proliferation was assessed by MTT, colony formation and cell cycle assays. Cell apoptotic rate was measured by flow cytometry via double-staining of Annexin V-FITC and PI. The protein expression patterns of forkhead box f1 (FOXF1) and enhancer of zeste homolog 2 (EZH2) were detected using western blot assays. The subcellular location of PVT1 was analyzed using subcellular fractionation assays. The interaction between PVT1 and EZH2 were demonstrated by RNA-protein pull down and RIP assays. ChIP assay was used to explore whether PVT1 affected FOXF1 expression by recruiting EZH2. In vivo assays were performed to further investigate the roles of PVT1 in breast cancer tumorigenesis. Results: PVT1 expression was elevated in breast cancer tissues and cells. Moreover, higher PVT1 level was positively associated with aggressive pathological status and poor prognosis of breast cancer. PVT1 knockdown suppressed proliferation and induced apoptosis in breast cancer cells. PVT1 silenced FOXF1 expression by recruiting EZH2 to the promoter region of FOXF1, resulting in the increase of H3K27me3 level. EZH2 inhibitor EPZ005687 counteracted PVT1-mediated enrichment effect on H3K27me3 and EZH2 to FOXF1 promoter region. FOXF1 overexpression hampered proliferation and facilitated apoptosis in breast cancer cells. Furthermore, down-regulation of FOXF1 partly abrogated PVT1-knockdown-mediated anti-proliferation and pro-apoptosis effect in breast cancer cells. Finally, PVT1 deficiency suppressed tumor growth by promoting FOXF1 expression in vivo. Conclusion: PVT1 promoted cell proliferation and suppressed apoptosis by epigenetically silencing FOXF1 expression through EZH2 in breast cancer.