Clinicopathological characteristics and genomic profiling of pure mucinous breast cancer.

PURPOSE: Pure mucinous breast cancer (PMC) is a rare histological type with a favourable prognosis. However, cases with recurrence have been reported and diagnosed in clinical practice. The mechanisms underlying PMC recurrence remain unknown. In this study, we aimed to identify the prognostic factors associated with PMC. MATERIALS AND METHODS: A total of 166 patients diagnosed with PMC were included. We compared the clinicopathological characteristics between patients with and without recurrence. The 21-gene assay was performed in 10 patients with recurrence and 20 TNM stage-matched patients without recurrence. Whole-exon sequencing was performed in 12 PMC primary tumours and four positive lymph nodes (LNs). RESULTS: Tumour size, lymph node status and TNM staging differed significantly between recurrent group and non-recurrent group. And the 21-gene recurrence scores did not differ significantly between recurrent group and its TNM stage-matched non-recurrent group. The most frequently mutated genes in the primary tumours of regional LN-positive PMCs were ADCY10 (3/6) and SHANK3 (3/6), and they more recurrently harboured gains of 15q23, 17q23.2 and 20p11.21, and loss of 21p11.2. And these alterations were not detected in primary tumours of regional LN-negative PMCs. CONCLUSION: TNM stage is an important prognostic factor in PMC. Although we revealed that regional LN-positive PMCs show increased occurrence of duplication variants at 15q23, 17q23.2 and 20p11.21, and deletion variants at 21p11.2. Further investigation, including multi-omics studies, are needed and may provide additional insights into the nature of PMC.

Roles of Pyroptosis-Related Gene Signature in Prediction of Endometrial Cancer Outcomes.

Endometrial cancer (EC) is one of the most common gynecological malignancies in women, accompanied by the increasing incidence and decreasing age of onset. Pyroptosis plays an important role in the occurrence and development of malignant tumors. However, the relationship between pyroptosis-related genes and tumor prognosis remains unclear. In this study, analyzing the expression levels and survival data of 33 pyroptosis-related genes in the Cancer Genome Atlas (TCGA) between normal samples and tumor samples, we obtained six pyroptosis-related prognostic differentially expressed genes (DEGs). Then, through the least absolute shrinkage and selection operator (LASSO) regression analysis, a gene signature composed of six genes (GPX4, GSDMD, GSDME, IL6, NOD2 and PYCARD) was constructed and divided patients into high- and low-risk groups. Subsequently, Kaplan-Meier (KM) plot, receiver operating characteristic (ROC) curve and principal component analysis (PCA) in two cohorts demonstrated that the gene signature was an efficient independent prognostic indicator. The enrichment analysis and immune infiltration analysis indicated that the high-risk group generally has lower immune infiltrating cells and less active immune function. In short, we constructed and validated a pyroptosis-related gene signature to predict the prognosis of EC, which is correlated to immune infiltration and proposed to help the precise diagnosis and therapy of EC.

A Cholesterol Homeostasis-Related Gene Signature Predicts Prognosis of Endometrial Cancer and Correlates With Immune Infiltration.

Background: Endometrial cancer (EC) is one of the most common gynecological malignancies in women. Cholesterol metabolism has been confirmed to be closely related to tumor proliferation, invasion and metastasis. However, the correlation between cholesterol homeostasis-related genes and prognosis of EC remains unclear. Methods: EC patients from the Cancer Genome Atlas (TCGA) database were randomly divided into training cohort and test cohort. Transcriptome analysis, univariate survival analysis and LASSO Cox regression analysis were adopted to construct a cholesterol homeostasis-related gene signature from the training cohort. Subsequently, Kaplan-Meier (KM) plot, receiver operating characteristic (ROC) curve and principal component analysis (PCA) were utilized to verify the predictive performance of the gene signature in two cohorts. Additionally, enrichment analysis and immune infiltration analysis were performed on differentially expressed genes (DEGs) between two risk groups. Results: Seven cholesterol homeostasis-related genes were selected to establish a gene signature. KM plot, ROC curve and PCA in two cohorts demonstrated that the gene signature was an efficient independent prognostic indicator. The enrichment analysis and immune infiltration analysis indicated that the high-risk group generally had lower immune infiltrating cells and immune function. Conclusion: We constructed and validated a cholesterol homeostasis-related gene signature to predict the prognosis of EC, which correlated to immune infiltration and expected to help the diagnosis and precision treatment of EC.

Miller-Payne Grading and 70-Gene Signature Are Associated With Prognosis of Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Early-Stage Breast Cancer After Neoadjuvant Chemotherapy.

INTRODUCTION: HR+/HER2- breast cancer (BC) has a much lower pathological complete response (pCR) rate to neoadjuvant chemotherapy (NAC). Therefore, to better stratify the relapse risk for HR+/HER2- non-pCR populations, it is essential to accurate identification new prognostic markers. MATERIALS AND METHODS: The study retrospectively analyzed 105 stage II-III patients who were diagnosed with HR+/HER2- BC and received NAC followed by breast and axilla surgery between 2013 and 2019 in Sun Yat-Sen University Cancer Center. The Miller-Payne (MP) grading system was used to evaluate pathological responses to NAC. The 70-gene signature was used to classify the prognosis signatures. RESULTS: Among the 105 patients, the study demonstrated that larger tumor size and lower progesterone receptor level at baseline and larger tumor size postoperative were statistically significantly associated with worse disease-free survival (DFS) (p = 0.004, p = 0.021, and p = 0.001, respectively). Among 54 patients who underwent the 70-gene assays, 26 (48.1%) had a low-risk signature; 28 (51.9%) patients had a high-risk signature. Patients with poor response (MP grades 1-2) were more likely to with a high-risk 70-gene signature than those with good response (MP grades 4-5). The final analysis showed that DFS was longer in the low-risk group than in the high-risk group [52.4 vs. 36.1 months of the median DFS, hazard ratio (HR) for recurrence, 0.29; 95% confidence interval (CI), 0.10-0.80; p = 0.018]. DFS was longer in the good response (MP grades 3-4) group than in the poor response (MP grades 1-2) group (94.7% vs. 60% of the patients free from recurrence; HR, 0.16; 95% CI, 0.05-0.47; p = 0.037). When stratified by MP grades combined with the 70-gene signature, subgroup analyses showed the good-response low-risk group with the best DFS, whereas the poor-response high-risk group showed the worst DFS (p = 0.048). Due to the short median follow-up time of 34.5 months (5.9-75.1 months), MP grades and the 70-gene signature did not show significant prognostic value for overall survival. CONCLUSION: The study showed that analysis of MP grades combined with the 70-gene signature with residual NAC-resistant breast samples has a significant correlation with DFS.

Clinical genomic profiling to identify actionable alterations for very early relapsed triple-negative breast cancer patients in the Chinese population.

BACKGROUND: Triple-negative breast cancer (TNBC) represents about 19% of all breast cancer cases in the Chinese population. Lack of targeted therapy contributes to the poorer outcomes compared with other breast cancer subtypes. Comprehensive genomic profiling helps to explore the clinically relevant genomic alterations (CRGAs) and potential therapeutic targets in very-early-relapsed TNBC patients. METHODS: Formalin-fixed paraffin-embedded (FFPE) tumour tissue specimens from 23 patients with very-early-relapsed TNBC and 13 patients with disease-free survival (DFS) more than 36 months were tested by FoundationOne CDx (F1CDx) in 324 genes and select gene rearrangements, along with genomic signatures including microsatellite instability (MSI) and tumour mutational burden (TMB). RESULTS: In total, 137 CRGAs were detected in the 23 very-early-relapsed TNBC patients, averaging six alterations per sample. The mean TMB was 4 Muts/Mb, which was higher than that in non-recurrence patients, and is statistically significant. The top-ranked altered genes were TP53 (83%), PTEN (35%), RB1 (30%), PIK3CA (26%) and BRCA1 (22%). RB1 mutation carriers had shorter DFS. Notably, 100% of these patients had at least one CRGA, and 87% of patients had at least one actionable alteration. In pathway analysis, patients who carried a mutation in the cell cycle pathway were more likely to experience very early recurrence. Strikingly, we detected one patient with ERBB2 amplification and one patient with ERBB2 exon20 insertion, both of which were missed by immunohistochemistry (IHC). We also detected novel alterations of ROS1-EPHA7 fusion for the first time, which has not been reported in breast cancer before. CONCLUSIONS: The comprehensive genomic profiling can identify novel treatment targets and address the limited options in TNBC patients. Therefore, incorporating F1CDx into TNBC may shed light on novel therapeutic opportunities for these very-early-relapsed TNBC patients.

Safety, tolerability, and pharmacokinetics of BAT8001 in patients with HER2-positive breast cancer: An open-label, dose-escalation, phase I study.

BACKGROUND: The introductions of anti- human epidermal growth factor receptor-2 (HER2) agents have significantly improved the treatment outcome of patients with HER2-positive breast cancer. BAT8001 is a novel antibody-drug conjugate targeting human epidermal growth factor receptor-2 (HER2)-expressing cells composed of a trastuzumab biosimilar linked to the drug-linker Batansine. This dose-escalation, phase I study was designed to assess the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of BAT8001 in patients with HER2-positive locally advanced or metastatic breast cancer. METHODS: This trial was conducted in subjects with histologically confirmed HER2-positive breast cancer (having evaluable lesions and an Eastern Cooperative Oncology Group performance status of 0 or 1) using a 3 + 3 design of escalating BAT8001 doses. Patients received BAT8001 intravenously in a 21-day cycle, with dose escalation in 5 cohorts: 1.2, 2.4, 3.6, 4.8, and 6.0 mg/kg. The primary objective was to evaluate the safety and tolerability of BAT8001. Preliminary activity of BAT8001 was also assessed as a secondary objective. RESULTS: Between March 2017 to May 2018, 29 HER2-positive breast cancer patients were enrolled. The observed dose-limiting toxicities were grade 4 thrombocytopenia and grade 3 elevated transaminase. The maximum tolerated dose was determined to be 3.6 mg/kg. Grade 3 or greater adverse events (AEs) occurred in 14 (48.3%) of 29 patients, including thrombocytopenia in 12 (41.4%) patients, aspartate aminotransferase increased in 4 (13.8%) patients, γ-glutamyl transferase increased in 2 (6.9%) patients, alanine aminotransferase increased in 2 (6.9%) patients, diarrhea in 2 (6.9%) patients. Objective response was observed in 12 (41.4%; 95% confidence interval [CI] = 23.5%-61.1%) and disease control (including patients achieving objective response and stable disease) was observed in 24 (82.8%; 95% CI = 64.2%-94.2%) patients. CONCLUSIONS: BAT8001 demonstrated favorable safety profiles, with promising anti-tumor activity in patients with HER2-positive locally advanced or metastatic breast cancer. BAT8001 has the potential to provide a new therapeutic option in patients with metastatic HER2-positive breast cancer.

Identification and characterization of critical genes associated with tamoxifen resistance in breast cancer.

BACKGROUND: Tamoxifen resistance in breast cancer is an unsolved problem in clinical practice. The aim of this study was to determine the potential mechanisms of tamoxifen resistance through bioinformatics analysis. METHODS: Gene expression profiles of tamoxifen-resistant MCF-7/TR and MCF-7 cells were acquired from the Gene Expression Omnibus dataset GSE26459, and differentially expressed genes (DEGs) were detected with R software. We conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses using Database for Annotation, Visualization and Integrated Discovery. A protein-protein interaction (PPI) network was generated, and we analyzed hub genes in the network with the Search Tool for the Retrieval of Interacting Genes database. Finally, we used siRNAs to silence the target genes and conducted the MTS assay. RESULTS: We identified 865 DEGs, 399 of which were upregulated. GO analysis indicated that most genes are related to telomere organization, extracellular exosomes, and binding-related items for protein heterodimerization. PPI network construction revealed that the top 10 hub genes-ACLY, HSPD1, PFAS, GART, TXN, HSPH1, HSPE1, IRAS, TRAP1, and ATIC-might be associated with tamoxifen resistance. Consistently, RT-qPCR analysis indicated that the expression of these 10 genes was increased in MCF-7/TR cells comparing with MCF-7 cells. Four hub genes (TXN, HSPD1, HSPH1 and ATIC) were related to overall survival in patients who accepted tamoxifen. In addition, knockdown of HSPH1 by siRNA may lead to reduced growth of MCF-7/TR cell with a trend close to significance (P = 0.07), indicating that upregulation of HSPH1 may play a role in tamoxifen resistance. CONCLUSION: This study revealed a number of critical hub genes that might serve as therapeutic targets in breast cancer resistant to tamoxifen and provided potential directions for uncovering the mechanisms of tamoxifen resistance.

PUF60/AURKA Axis Contributes to Tumor Progression and Malignant Phenotypes in Bladder Cancer.

Abnormal expression or mutation of RNA splicing proteins are widely observed in human cancers. Here, we identified poly(U) binding splicing factor 60 (PUF60) as one of the most differentially expressed genes out of 97 RNA splicing proteins between normal and bladder cancer tissues by bioinformatics analysis of TCGA bladder cancer expression data. The expression of PUF60 was significantly higher in tumor tissues, while high PUF60 expression was associated with malignant phenotypes of bladder cancer and shorter survival time. Moreover, we identified aurora kinase A (AURKA) as a new downstream target of PUF60 in bladder cancer cells. PUF60 knockdown significantly inhibited cell viability and colony formation capacity in bladder cancer cells, whereas AURKA overexpression reversed this inhibition effect. Overexpression of PUF60 significantly promoted cell viability and colony formation in bladder cancer cells, while treatment with AURKA specific inhibitor reversed this promotive effect. Mechanistically, PUF60 specifically bound to the AURKA promoter, thereby activating its transcription and expression. Furthermore, we showed that there was a significant positive correlation between PUF60 and AURKA expression in bladder cancer tissues, and PUF60 and AURKA expression contributed to tumor progression and malignant phenotypes in the patients with bladder cancer. Collectively, these results indicate that the PUF60/AURKA axis plays a key role in regulating tumorigenesis and progression of bladder cancer, and may be a potential prognostic biomarker and therapeutic target for bladder cancer patients.

ClC-3/SGK1 regulatory axis enhances the olaparib-induced antitumor effect in human stomach adenocarcinoma.

Currently, only a few available targeted drugs are considered to be effective in stomach adenocarcinoma (STAD) treatment. The PARP inhibitor olaparib is a molecularly targeted drug that continues to be investigated in BRCA-mutated tumors. However, in tumors without BRCA gene mutations, particularly in STAD, the effect and molecular mechanism of olaparib are unclear, which largely restricts the use of olaparib in STAD treatment. In this study, the in vitro results showed that olaparib specifically inhibited cell growth and migration, exerting antitumor effect in STAD cell lines. In addition, a ClC-3/SGK1 regulatory axis was identified and validated in STAD cells. We then found that the down-regulation of ClC-3/SGK1 axis attenuated olaparib-induced cell growth and migration inhibition. On the contrary, the up-regulation of ClC-3/SGK1 axis enhanced olaparib-induced cell growth and migration inhibition, and the enhancement effect could be attenuated by SGK1 knockdown. Consistently, the whole-cell recorded chloride current activated by olaparib presented the same variation trend. Next, the clinical data showed that ClC-3 and SGK1 were highly expressed in human STAD tissues and positively correlated (r = 0.276, P = 0.009). Furthermore, high protein expression of both ClC-3 (P = 0.030) and SGK1 (P = 0.006) was associated with poor survival rate in STAD patients, and positive correlations between ClC-3/SGK1 and their downstream molecules in STAD tissues were demonstrated via the GEPIA datasets. Finally, our results suggested that olaparib inhibited the PI3K/AKT pathway in STAD cells, and up-regulation of ClC-3/SGK1 axis enhanced olaparib-induced PI3K/AKT pathway inhibition. The animal experiments indicated that olaparib also exerted antitumor effect in vivo. Altogether, our findings illustrate that olaparib exerts antitumor effect in human STAD, and ClC-3/SGK1 regulatory axis enhances the olaparib-induced antitumor effect. Up-regulation of the ClC-3/SGK1 axis may provide promising therapeutic potential for the clinical application of olaparib in STAD treatment.

Metronomic chemotherapy of cyclophosphamide plus methotrexate for advanced breast cancer: Real-world data analyses and experience of one center.

BACKGROUND: Real-world data of the CM regimen [cyclophosphamide (CTX) plus methotrexate (MTX)] in metronomic pattern for advanced breast cancer is limited to small-sample or retrospective studies. This study was aimed to determine the effectiveness and safety of CM regimen in treating advanced breast cancer and to identify which patients are most likely to benefit from metronomic CM regimen. METHODS: Patients with advanced breast cancer who received the metronomic CM regimen at least once between January 2009 and February 2019 in Sun Yat-sen University Cancer Center were included. Clinicopathological characteristics were collected. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier estimates. Characteristics between patients with PFS < 6 months and ≥6 months were compared using the Chi-square test. Univariate and multivariate Cox regression model was used to estimate the prognostic factors for PFS and OS. RESULTS: A total of 186 patients were included. The median age and follow-up were 49 years and 13.3 months, respectively. Over 50% of the patients were estrogen receptor/progesterone receptor-positive, and 60.8% had been heavily treated (≥3 lines). The objective response rate was 3.8%, the disease control rate at 12 weeks was 41.4%, and the clinical benefit rate at 24 weeks was 31.2% (58/186). The median PFS was 4.0 months [95% confidence interval (CI): 3.6-4.7 months], the median duration of clinical benefit was 9.5 months (95% CI: 8.2-10.8 months), and the median OS was 26.8 months (95% CI: 20.9-37.7 months). Multivariate analysis for PFS revealed the CM regimen as maintenance therapy and no liver metastasis as favorable prognostic factors. Furthermore, patients without liver metastasis were more likely to have a PFS over 6 months than those with liver involvement (P = 0.022). Liver, lymph node, and brain metastases were unfavorable prognostic factors for OS. The CM regimen was well-tolerated without newly reported adverse events. CONCLUSIONS: The CM regimen was effective in selected patients. In clinical practice, it would be better used as maintenance therapy and in patients without liver metastasis. Further follow-up investigation should be performed to examine its effect when used in combination with other treatments and determine predictive biomarkers.

Administration of Lapatinib with Food Increases Its Plasma Concentration in Chinese Patients with Metastatic Breast Cancer: A Prospective Phase II Study.

LESSONS LEARNED: Administration of lapatinib with food significantly increased its plasma concentration in Chinese patients with metastatic breast cancer. There were no serious adverse events during the study and no significant differences in lapatinib-related adverse events between the fasted and fed states. BACKGROUND: Lapatinib, a small molecular reversible dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth receptor 2 (HER2), was approved for use in combination with capecitabine to treat metastatic HER2-positive breast cancer. Administration of lapatinib in the fasted state was recommended; however, our preliminary phase II trial data showed that administration of lapatinib with food increased its concentration. METHODS: This study was a single-center, open-label, and prospective self-controlled clinical study. Ten Chinese patients with metastatic breast cancer were enrolled from June 2017 to April 2018. They were required to receive lapatinib plus physician's choice of chemotherapy. Patients were required to take lapatinib orally on an empty stomach continually for 10 days, and then take lapatinib with food continually for the next 10 days. Plasma concentration was measured by liquid chromatography on the 9th and 10th day of each state. RESULTS: Area under the concentration-time curve (AUC) of the fasted state and the fed state was 21.23 ± 8.91 mg*h/L (coefficient of variation (CV)% 42%) and 60.60 ± 16.64 mg*h/L (CV% 27%), respectively. The mean plasma concentration in the fasted state was 0.88 ± 0.39 mg/L (CV% 45%), and that in the fed state was 2.53 ± 0.77 mg/L (CV% 30%). Compared with taking lapatinib on an empty stomach, receiving lapatinib with food significantly increased the plasma concentration of lapatinib (Wilcoxon match-paired test, p = .005). In addition, there were no serious adverse events during the study or significant difference in lapatinib-related adverse events between the two states. CONCLUSION: Our study shows that receiving lapatinib with food can increase its plasma concentration with no significantly increased drug-related toxicity. We suggest that a larger-sample-size clinical trial is needed to fully understand the effect of administration of lapatinib with food.

Local treatment for liver oligometastases in breast cancer patients: identification of prognostic factors and exploration of appropriate treatment strategy.

BACKGROUND: The role of local treatment for liver oligometastases in breast cancer patients has been controversial. The aim of the study was to evaluate the prognostic factors for overall survival (OS) and progression-free survival (PFS) after hepatic local treatment and to explore appropriate therapy strategy in breast cancer patients with liver oligometastases. METHODS: A cohort of 91 patients with oligometastatic liver lesions identified from around 34,000 breast cancer patients between 2002 and 2018 were retrospectively reviewed. We collected and analyzed their clinicopathologic and outcome data. RESULTS: With a median follow up of 20.6 months [standard deviations (SD): 35.4], median OS and median PFS were 75.1 months [95% confidence interval (CI): 14.3-135.9 months] and 7.4 months (95% CI: 4.4-10.4 months), respectively. N3 stage, triple-negative breast cancer (TNBC) subtype, progressive disease (PD) after preoperative systemic therapy and older age of operation were associated with worse OS and PFS while postoperative systemic therapy alone, preoperative [partial response (PR)/stable disease (SD)] combined with postoperative systemic therapy indicated improved OS and PFS by univariate analysis. On multivariate analysis, N3 stage [hazard ratios (HR) 23.567; 95% CI: 1.751-317.277; P=0.017] and TNBC subtype (HR 10.758; 95% CI: 1.120-103.301; P=0.040) were related to worse OS. Likewise, N3 stage (HR 3.324; 95% CI 1.604-6.890; P=0.001) and TNBC subtype (HR 3.134; 95% CI: 1.015-9.674; P=0.047) remained associated with worse PFS. The postoperative mortality and morbidity were 0% and 1.099%, respectively. CONCLUSIONS: In well-selected patients, local treatment of breast cancer liver oligometastases is safe and achieves relatively long OS, except patients with advanced N stage or aggressive subtype. Postoperative systemic treatment and effective preoperative systemic therapy combined with postoperative systemic therapy are the recommended treatment strategies.

Bicalutamide plus Aromatase Inhibitor in Patients with Estrogen Receptor-Positive/Androgen Receptor-Positive Advanced Breast Cancer.

LESSONS LEARNED: Studies targeting the androgen receptor (AR) signaling pathway in aromatase inhibitor (AI)-resistant breast cancer are limited. Bicalutamide, one of the commonly used AR inhibitors in prostate cancer, in combination with AI, did not show synergistic activity in patients with estrogen receptor-positive and AI-resistant disease in this phase II, single-arm study. The clinical benefit rate and objective response rate at 6 months were 16.7% and 0%, respectively, and the study was terminated after the first stage. BACKGROUND: Endocrine resistance is a major problem in clinical practice. Studies have shown that androgen receptor (AR) signaling activation may be one of the mechanisms, and targeting AR showed some promising results in AR-positive triple-negative breast cancer. The aim of this study was to assess the efficacy and safety of bicalutamide plus another aromatase inhibitor in patients with nonsteroidal aromatase inhibitor (AI) or steroidal AI resistance and estrogen receptor (ER)-positive and AR-positive advanced breast cancer. METHODS: A Simon's two-stage, phase II, single-arm study was conducted. We assumed the clinical benefit rate (CBR) of 40% would be significant in clinical practice. In this case, if ≥4 patients of the 19 patients in the first stage benefited from treatment, the CBR would achieve the assumed endpoint. If fewer than four patients benefited from treatment in the first stage, the trial would be terminated. All patients received bicalutamide 50 mg per day orally plus another aromatase inhibitor. The primary outcome was CBR; secondary outcomes included objective response rate (ORR), progression-free survival (PFS), and tolerability. RESULTS: A total of 19 patients enrolled in the first stage, and 18 patients met all criteria for analysis. The trial terminated according to protocol after the first stage. After a median follow-up of 14 months, the CBR at 6 months was 16.7% (3/18); no patients with partial or complete response were observed. The median PFS was 2.7 months. Bicalutamide in combination with AI was well tolerated. CONCLUSION: Bicalutamide in combination with another AI did not show synergistic activity in patients with ER-positive breast cancer and AI resistance. Results suggest that no more large-sample clinical trials should be conducted in this population for overcoming endocrine resistance.

Panobinostat (LBH589) inhibits Wnt/ß-catenin signaling pathway via upregulating APCL expression in breast cancer.

Breast cancer is the most common malignant disease among women worldwide and the novel therapeutic agents are urgently needed. Panobinostat (LBH589), a pan-HDACs inhibitor, has shown promising anti-tumor effect in recent years. However, the targets of this compound are largely unclear because of its low selectivity. In consideration of the transcription promoting activity of panobinostat, we speculated that specific tumor suppressor genes might be upregulated after panobinostat treatment. In this study, we verified the inhibition effect of panobinostat in different subtypes of breast cancer cells in vivo and in vitro. We found that panobinostat suppressed proliferation, migration as well as invasion, and induced apoptosis in both TNBC and non-TNBC cells. Consistently, panobinostat inhibited breast cancer growth and metastasis in mouse models. Mechanistically, we found APCL transcription and expression was significantly upregulated in panobinostat treated cells by RNA microarray analysis, while knockdown of APCL resulted in reduced sensitivity to panobinostat in breast cancer cells. APCL is a wnt/ß-catenin pathway regulator that promotes ß-catenin ubiquitylation and degradation. We found that panobinostat inhibited ß-catenin expression by increasing its ubiquitylation and thus reducing its half-life. In addition, the expression of ß-catenin activated targets including c-Jun, c-Myc, Cyclin D1 and CD44 were also decreased by panobinostat treatment in breast cancer cells. These results suggested that panobinostat inhibited tumor growth and metastasis via upregulating APCL expression in breast cancer cells, which was a novel and crucial mechanism of panobinostat.