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Background: Neoadjuvant chemotherapy (NAC) has evolved significantly and has been widely accepted for downstaging disease in early-stage and locally advanced breast cancer patients. Since the optimal surgical intervention of the breast for patients receiving NAC remains controversial, we aim to investigate the survival outcome of patients treated with different surgical management. Methods: Patients with invasive breast cancer that underwent NAC in Fudan University Shanghai Cancer Center from January 2010 to June 2019 were involved in this study. Based on surgical intervention of the breast following NAC, patients were divided into mastectomy and breast conservation groups. To be specific, the mastectomy group involved patients who received mastectomy alone or mastectomy plus immediate breast reconstruction (M+IBR), while the breast conservation group evolved patients who underwent conventional breast-conserving surgery (CBCS) and oncoplastic surgery (OPS). Surgical interventions were performed by breast surgeons. Propensity scores matching was utilized for group matching. Results: A total of 2080 patients were enrolled in this study. Among them, 1819 (87.5%) patients were categorized as mastectomy group, and 261 (12.5%) patients were classed as breast conservation group. In the mastectomy group, mastectomy alone and M+IBR accounted for 82.5% (1715/2080) and 5% (104/2080) patients respectively. As for breast conservation, 170 (8.2%) and 91 (4.4%) patients were treated with CBCS and OPS after NAC. Over 9-years of research, the proportion of breast conservation steadily increased in patients after NAC. Notably, the percentage of patients undergoing OPS increased from 0.43 % to 7.60 % throughout the 9 years. Moreover, increasing rate of M+IBR was also observed in the study cohort, whereas fewer patients opted for mastectomy alone as surgical intervention after NAC. Compared with mastectomy group, patients underwent BCS showed younger age (P < 0.001), as well as higher proportion of normal BMI (P = 0.022), pre-menopausal status (P < 0.001), and triple-negative breast cancer (P < 0.008). Additionally, patients with tumors of advanced clinical T stage (P < 0.001) and TNM stage (P = 0.002) were more often to be treated with mastectomy (Table 1). After propensity score matching, 460 patients were matched successfully (Table 2). Compared with the mastectomy group, significant benefits in overall survival (Hazard ratio 0.51, [95% confidence interval: 0.27-0.96]; p=0.044) and disease-free survival (Hazard ratio 0.62, [95% confidence interval: 0.39-0.99]; p Conclusions: Tumor biology can significantly impact the surgical decision in patients administrated with NAC. Breast conservation was a safe alternative for mastectomy in the NAC setting without compromising survival outcomes. Table 1. Clinicopathologic characteristics of patients in mastectomy and breast conservation groups. Table 2. Balanced statistics of patients receiving mastectomy and breast conservation after propensity score matching. Table 3. Survival analysis between matched cohort of patients receiving mastectomy (n=230), breast-conserving therapy (n=230). Citation Format: Yuting Sang, Jiajian Chen, Benlong Yang, Shuang Hao, Xiaoyan Huang, Guangyu Liu, Zhimin Shao, Jiong Wu. Surgical options of the breast and clinical outcomes in breast cancer patients after neoadjuvant chemotherapy: a single-center retrospective study. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-14-02.

Background: Female breast cancer has been the world’s leading cancer incidence among women. HER2-positive breast cancer accounts for about 15%~20% of all breast cancer, with a high degree of malignancy and easy metastasis and recurrence. With the development of medical technology and the continuous innovation of HER2 targeting drugs, patients with HER2-positive breast cancer have more treatment options and their prognosis had been greatly improved. However, there is still a lack of biomarkers for HER2-positive early breast cancer in clinical practice. Methods: This study prospectively collected single-center (Fudan University Shanghai Cancer Center, FUSCC) preoperative core needle biopsy samples of breast cancer patients from July 2017 to July 2018 who received neoadjuvant paclitaxel, carboplatin plus with trastuzumab (PCH). The patients were divided into pCR and non-PCR groups, and 81 patients were enrolled. The differential expression of genes was screened and validated by RNA-seq. The gene expression data for GSE181574 (this database has a total of 105 cases of breast cancer tissue samples were collected by core needle biopsy before neoadjuvant treatment. 52 cases underwent Ado-trastuzumab emtansine plus pertuzumab, 9 cases of paclitaxel plus trastuzumab, and 44 cases of paclitaxel plus trastuzumab and pertuzumab), GSE52707 (SK-BR-3 Lapatinib resistance cell group vs control group), and GSE15043 (BT474 Herceptin-resistant cell group vs control group), were downloaded from the Gene Expression Omnibus (GEO) database. Cell cloning formation, proliferation assay, and drug sensitivity experiments were conducted in MNX1 ectopic and knockdown cell lines. Co-IP assay, RNA-Seq, and ChIP-Seq analysis were used to explore the downstream pathways that MNX1 might be involved. Results: High-throughput sequencing results of core needle biopsy samples from 81 HER2-positive breast cancer patients were divided into pCR and non-pCR groups. Using DEseq2 packet analysis to screen differentially expressed genes, P-value < 0.05, | log2FoldChange | > 1 as the filter, there were 620 up-regulated genes and 715 down-regulated genes in the pCR group. The same method was used for the analysis of the GSE181574 data set. Combined the two datasets used P values and log2FoldChange (P-value < 0.05, | log2FoldChange | > 1.2) as selection criteria, we found the MNX1 and PNMT expressions were significantly higher in the pCR group. Subsequently, differential analysis of GSE52707 and GSE15043 datasets showed that MNX1 and PNMT expression levels were reduced in drug-resistant cell lines. Considering the P-value and | log2FoldChange |, we ultimately selected motor neuron and pancreatic homeobox 1(MNX1) gene as the target factors for follow-up studies. In the cloning formation and proliferation assay, overexpression of MNX1 inhibits proliferation and clonal formation of HER2-positive breast cancer cells. In the drug sensitivity experiments overexpression of MNX1 enhances the sensitivity of HER2-positive breast cancer cells to tyrosine kinase inhibitors (TKI) such as lapatinib and pyrotinib. MNX1 knockdown reduces the sensitivity of HER2-positive breast cancer cells to TKI. Through RNA-seq and ChIP-seq, we found that CD-M6PR might be a downstream target gene regulated by MNX1. Verification by Dual-Luciferase Reporter Assay MNX1 was found to positively regulate CD-M6PR transcription. By Co-IP assay, it was found that MNX1 interacted with EEF1D, and EEF1D stabilized MNX1. MNX1 and CD-M6PR affect the proliferation and drug sensitivity of breast cancer cells by down-regulating the PI3K-AKT-mTOR pathway. Conclusion: Overexpression of MNX1 increases the sensitivity of HER-2 positive cells to TKI. MNX1 binds to EEF1D and is stabilized by EEF1D. MNX1 positively regulates M6PR and affects the proliferation of breast cancer cells and the sensitivity of breast cancer cells to TKI through the PI3K-AKT-mTOR pathway. Citation Format: Wei-Ru Chi, Bingqiu Xiu, Min Xiong, Pei Li, Qi Zhang, Lun Li, Jianjing Hou, Xujie Zhou, Yuting Sang, Ming Chen, Liyi Zhang, Jingyan Xue, Yayun Chi, Jiong Wu. MNX1 promotes tumor sensitivity to HER2-targeted therapy in HER2-positive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-16-04.

Associations between NAMPT-AS level and clinico-pathological characteristics in TCGA breast cancer patients

The file contains 9 supplementary Figures indicating the bioinformatics analysis, transfection efficiency analysis, rescue experiments and clinical sample analysis.

Triple-negative breast cancer (TNBC) is highly heterogeneous and has a poor prognosis. It is therefore important to identify the underlying molecular mechanisms in order to develop novel therapeutic strategies. Although emerging research has revealed long noncoding RNAs (lncRNA) as vital to carcinogenesis and cancer progression, their functional involvement in TNBC has not been well defined. In this study, we utilized the The Cancer Genome Atlas (TCGA) database and analyzed clinical samples to show that the long noncoding antisense transcript of nicotinamide phosphoribosyltransferase (NAMPT), NAMPT-AS, is upregulated in TNBC and is associated with poor prognosis, lymph node involvement, metastasis, and advanced stage. NAMPT-AS was cotranscribed with NAMPT from a bidirectional promoter, where the distributions of H3K4me3 and H3K27Ac chromatin modifications were enriched based on ENCODE and FANTOM5, suggesting the potential enhancer-RNA characteristics of NAMPT-AS. NAMPT-AS epigenetically regulated the expression of NAMPT in two divergent ways: NAMPT-AS recruited POU2F2 to activate the transcription of NAMPT, and NAMPT-AS acted as a competing endogenous RNA to rescue NAMPT degradation from miR-548b-3p. NAMPT-AS/NAMPT promoted tumor progression and regulated autophagy through the mTOR pathway in vitro and in vivo. In a cohort of 480 breast cancer patients, NAMPT was associated with breast cancer–specific survival and overall survival. These results demonstrate that NAMPT-AS is an oncogenic lncRNA in TNBC that epigenetically activates NAMPT to promote tumor progression and metastasis. Furthermore, these data identify NAMPT-AS/NAMPT as promising therapeutic targets in patients with TNBC.Significance:Upregulation of the long noncoding antisense RNA of NAMPT gene (NAMPT-AS) is associated with metastasis and poor prognosis in TNBC.

Background: Neoadjuvant therapy is an important part of treatments for patients with locally advanced operable breast cancer. Addition of HER2 targeted therapy to neoadjuvant therapy greatly improves the pathological complete response (pCR) and prognosis in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. As the essential markers for targeted therapy decision, HER2 status was reported that might be loss in patients undergo neoadjuvant therapy. Therefore, we evaluated the ratio of HER2 loss and its prognostic impact in HER2-positive breast cancer patients treated with neoadjuvant therapy in a large cohort.Methods: A total of 706 patients with HER2-positive breast cancer without distant metastasis who were diagnosed at the Department of Breast Surgery of Fudan University Cancer Hospital from September 2013 to January 2020 and received neoadjuvant treatment were enrolled in the study. After the neoadjuvant treatment, all patients underwent breast surgery. Patients who did not achieve complete pathological remission (non-PCR) would assess the discordance rate of HER2 status between pre- and post-treatment specimens. The expression of HER2 was assessed by immunohistochemistry or combined with fluorescence in situ hybridization (FISH).Results: 35.5.% (n=251) of HER2-positive breast cancer patients who received neoadjuvant therapy achieved pCR. They have prolonged overall survival than who did not achieve pCR (non-pCR) (hazard ratio [HR], 0.26; P = 0.0068). 83.5% (380/455) of the residual tumor lesions were re-tested by immunohistochemistry in non-PCR group. Among them, patients with loss of HER2 positivity accounted for 18.15% (n=69). The rate of HER2 loss was evaluated separately according to baseline status. In IHC 3+ group, 90.7% (258/289) patients remained as HER2 positive after treatment; In IHC 2+ group, 89.3% (47/78) were still HER2 positive while in IHC result 1+ group, 41.7% (5/12) were identified as HER2 positive. The loss of HER2 expression was significantly related to the baseline low HER2 expression (P Clinicopathological characteristics of HER2-positive breast cancer patients.Characteristics No. (%)No. of patients706Age at diagnosis, Median (range, years)59 (23-75)cT stageT04 (0.6)T193 (13.2)T2452 (64.0)T3109 (15.4)T448 (6.8)cN stageN081 (11.5)N1/N2506 (71.7)N3119 (16.8)ER statusPositive636 (90.1)Negative70 (9.9)PR statusPositive615 (87.1)Negative91 (12.9)HER2 statusIHC 3+, FISH-positive481 (68.12)IHC 3+, N/A98 (13.9)IHC 2+, FISH-positive113 (16.0)IHC 1+, FISH-positive14 (1.98) HER2 status before and after neoadjuvant therapy in patients with HER2-positive breast cancer.Primary tumorn (%)Residual tumorn (%)HER2 statusHER2 statusPositive379 (100)Positive304 (80.2)Negative75 (19.8)HER2 status identified by IHCHER2 status identified by IHCHER2 3+289 (76.3)HER2 3+249 (86.2)HER2 2+31 (10.7)HER2 1+6 (2.1)HER2 03 (1.0)HER2 2+HER2 3+14 (17.9)HER2 2+53 (67.9)HER2 1+9 (11.5)HER2 02 (2.6)HER2 1+HER2 3+2 (16.7)HER2 2+3 (25.0)HER2 1+5 (41.7)HER2 02 (16.7) Citation Format: Yuting Sang, Jiong Wu, Benlong Yang. Loss of HER2 expression in HER2-positive breast cancer patients after neoadjuvant therapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-20.

Circular RNA (circRNA), as a kind of novel identified non-coding RNA, has become the focus of attention for its vital physiological and pathological roles. However, the function and mechanism of circRNAs in the regulation of cancer progression are largely unknown. In the present study we found a circRNA termed circHMCU whose expression was associated with poor prognosis. It was upregulated in cell lines with high metastatic potential compared with its parental cell line and in breast cancer tissues compared with normal tissues. In vitro results proved that circHMCU could significantly promote proliferation, migration, and invasion abilities of breast cancer cells via affecting the G1 phase cell cycle checkpoint and the epithelial-mesenchymal transition (EMT) pathway. Further in vivo studies showed that overexpression of circHMCU contributed to rapid proliferation and lung metastasis of breast cancer. For determination of the mechanisms, bioinformatics analysis revealed two complementary sequences within circHMCU for let-7 microRNAs, which was validated by a luciferase reporter assay. Finally, let-7 microRNAs could rescue the functions of circHMCU in breast cancer via suppressing the expression of MCY, HMGA2, and CCND1. Taken together, our findings demonstrated that circHMCU exerted oncogenic functions in breast cancer and could be a used as a novel biomarker in the diagnosis and prognosis of breast cancer., Graphical Abstract, circHMCU promotes proliferation and metastasis of breast cancer by sponging the let-7 family and suppressing the expression of MCY, HMGA2, and CCND1, which could be a used as a novel biomarker in the diagnosis and prognosis of breast cancer.

Triple-negative breast cancer (TNBC) is highly heterogeneous and has a poor prognosis. It is therefore important to identify the underlying molecular mechanisms in order to develop novel therapeutic strategies. Although emerging research has revealed long noncoding RNAs (lncRNA) as vital to carcinogenesis and cancer progression, their functional involvement in TNBC has not been well defined. In this study, we utilized the The Cancer Genome Atlas (TCGA) database and analyzed clinical samples to show that the long noncoding antisense transcript of nicotinamide phosphoribosyltransferase (NAMPT), NAMPT-AS, is upregulated in TNBC and is associated with poor prognosis, lymph node involvement, metastasis, and advanced stage. NAMPT-AS was cotranscribed with NAMPT from a bidirectional promoter, where the distributions of H3K4me3 and H3K27Ac chromatin modifications were enriched based on ENCODE and FANTOM5, suggesting the potential enhancer-RNA characteristics of NAMPT-AS. NAMPT-AS epigenetically regulated the expression of NAMPT in two divergent ways: NAMPT-AS recruited POU2F2 to activate the transcription of NAMPT, and NAMPT-AS acted as a competing endogenous RNA to rescue NAMPT degradation from miR-548b-3p. NAMPT-AS/NAMPT promoted tumor progression and regulated autophagy through the mTOR pathway in vitro and in vivo. In a cohort of 480 breast cancer patients, NAMPT was associated with breast cancer-specific survival and overall survival. These results demonstrate that NAMPT-AS is an oncogenic lncRNA in TNBC that epigenetically activates NAMPT to promote tumor progression and metastasis. Furthermore, these data identify NAMPT-AS/NAMPT as promising therapeutic targets in patients with TNBC. SIGNIFICANCE: Upregulation of the long noncoding antisense RNA of NAMPT gene (NAMPT-AS) is associated with metastasis and poor prognosis in TNBC.

Emerging evidence suggests that circular RNAs (circRNAs) have crucial roles in various processes, including cancer development and progression. However, the functional roles of circRNAs in breast cancer remain to be elucidated. In this study, we identified a novel circRNA (named circBMPR2) whose expression was lower in breast cancer tissues with metastasis. Moreover, circBMPR2 expression was negatively associated with the motility of breast cancer cells and significantly downregulated in human breast cancer tissues. Functionally, we found that circBMPR2 knockdown effectively enhanced cell proliferation, migration, and invasion. Moreover, circBMPR2 knockdown promoted tamoxifen resistance of breast cancer cells through inhibiting tamoxifen-induced apoptosis, whereas circBMPR2 overexpression led to decreased tamoxifen resistance. Mechanistically, we demonstrated that circBMPR2 could abundantly sponge miR-553 and that miR-553 overexpression could attenuate the inhibitory effects caused by circBMPR2 overexpression. We also found that ubiquitin-specific protease 4 (USP4) was a direct target of miR-553, which functions as a tumor suppressor in breast cancer. Our findings demonstrated that circBMPR2 might function as a miR-553 sponge and then relieve the suppression of USP4 to inhibit the progression and tamoxifen resistance of breast cancer. Targeting this newly identified circRNA may help us to develop potential novel therapies for breast cancer patients. Keywords: breast cancer, circBMPR2, tumor suppressor, tamoxifen resistance, miR-553, USP4

Triple-negative breast cancer (TNBC) is highly heterogeneous and has a poor prognosis. It is therefore important to identify the underlying molecular mechanisms in order to develop novel therapeutic strategies. Although emerging research has revealed long noncoding RNAs (lncRNA) as vital to carcinogenesis and cancer progression, their functional involvement in TNBC has not been well defined. In this study, we utilized the The Cancer Genome Atlas (TCGA) database and analyzed clinical samples to show that the long noncoding antisense transcript of nicotinamide phosphoribosyltransferase (NAMPT), NAMPT-AS, is upregulated in TNBC and is associated with poor prognosis, lymph node involvement, metastasis, and advanced stage. NAMPT-AS was cotranscribed with NAMPT from a bidirectional promoter, where the distributions of H3K4me3 and H3K27Ac chromatin modifications were enriched based on ENCODE and FANTOM5, suggesting the potential enhancer-RNA characteristics of NAMPT-AS. NAMPT-AS epigenetically regulated the expression of NAMPT in two divergent ways: NAMPT-AS recruited POU2F2 to activate the transcription of NAMPT, and NAMPT-AS acted as a competing endogenous RNA to rescue NAMPT degradation from miR-548b-3p. NAMPT-AS/NAMPT promoted tumor progression and regulated autophagy through the mTOR pathway in vitro and in vivo. In a cohort of 480 breast cancer patients, NAMPT was associated with breast cancer–specific survival and overall survival. These results demonstrate that NAMPT-AS is an oncogenic lncRNA in TNBC that epigenetically activates NAMPT to promote tumor progression and metastasis. Furthermore, these data identify NAMPT-AS/NAMPT as promising therapeutic targets in patients with TNBC. Significance: Upregulation of the long noncoding antisense RNA of NAMPT gene (NAMPT-AS) is associated with metastasis and poor prognosis in TNBC.

Rapid proliferation and metastasis of breast cancers resulted in poor prognosis in clinic. Recent studies have proved that long noncoding RNAs (lncRNAs) were involved in tumor progression. In this study, we aimed to determine the roles and mechanisms of lncRNA-cell division cycle 6 (CDC6) in regulating proliferation and metastasis of breast cancer. Clinically, lncRNA-CDC6 was highly expressed in tumor tissues and was positively correlated with clinical stages of breast cancers. Functionally, the ectopic expression of lncRNA-CDC6 promoted proliferation via regulation of G1 phase checkpoint, and further promoting the migration capability. Moreover, lncRNA-CDC6 could function as competitive endogenous RNA (ceRNA) via directly sponging of microRNA-215 (miR-215), which further regulating the expression of CDC6. Taken together, our results proved that lncRNA-CDC6 could function as ceRNA and promote the proliferation and metastasis of breast cancer cells, which provided a novel prognostic marker for breast cancers in clinic.

Accumulating evidence indicates that long non-coding RNAs (lncRNAs) play a critical role in cancerous processes as either oncogenes or tumor suppressor genes. Here, we demonstrated that lncRNA-PRLB (progression-associated lncRNA in breast cancer) was upregulated in human breast cancer tissues and breast cancer cell lines. Further evaluation verified that lncRNA-PRLB was positively correlated with the extent of metastasis, and its expression was correlated with shorter survival time of breast cancer patients. We identified microRNA miR-4766-5p as an inhibitory target of lncRNA-PRLB. Both lncRNA-PRLB overexpression and miR-4766-5p knockdown could remarkably enhance cell growth, metastasis, and chemoresistance. We also determined that sirtuin 1 (SIRT1) was an inhibitory target of miR-4766-5p, and that SIRT1 was inhibited by both lncRNA-PRLB knockdown and miR-4766-5p overexpression. Significantly, we found that the promotion of cell proliferation and metastasis, the acquisition of chemoresistance, and the increased expression of SIRT1 induced by lncRNA-PRLB overexpression could be partly abrogated by ectopic expression of miR-4766-5p. Taken together, our findings indicated that lncRNA could regulate the progression and chemoresistance of breast cancer via modulating the expression levels of miR-4766-5p and SIRT1, which may have a pivotal role in breast cancer treatment and prognosis prediction.

Background and objectives Latissimus dorsi, an anatomical landmark for axillary lymph node dissection, was reported to harbor an anatomical variation named Langer's axillary arch (LAA). However, the incidence and clinical significance of LAA in breast cancer remain obscure. Methods We conducted a six-year prospective study, including 1724 breast cancer patients in Qilu hospital between January 2012 to February 2018. All patients received ALND were inspected for existence of LAA. All the surgeries were completed with the involvement of same experienced surgeon. Once the LAA was identified, all the lymph nodes located lateral to it, named LAA's lymph node, were dissected and collected for pathologic examination. Results Among 1724 breast cancer patients, LAA was identified in 132 patients (7.66%). 120 out of the 132 patients (90.91%) had at least two LAA's lymph nodes. 21 out of 120 patients (17.50%) were confirmed with cancer cell metastasis in LAA's lymph nodes. Among the 23 patients received sentinel lymph node tracing, sentinel lymph node was located lateral to LAA in 3 patients (13.04%). Conclusions Our results indicated that it is of great importance for surgeons to correctly ascertain LAA, and it should be taken as a nonnegligible parts during ALND or SLNB.

Increasing evidence has indicated that circular RNAs (circRNAs) play a critical role in cancer development. However, only a small number of circRNAs have been experimentally validated and functionally annotated. In this study, using a high-throughput microarray assay, we identified a novel circRNA, circKDM4C, which was downregulated in breast cancer tissues with metastasis. Furthermore, we analyzed a cohort of breast cancer patients and found that circKDM4C expression was decreased in breast cancer tissues, and lower circKDM4C expression was associated with poor prognosis and metastasis in breast cancer. Functionally, we demonstrated that circKDM4C significantly repressed breast cancer proliferation, metastasis, and doxorubicin resistance in vitro and in vivo. Mechanistically, using a dual-luciferase activity assay and AGO2 RNA immunoprecipitation, circKDM4C was identified as a miR-548p sponge. We also found that PBLD was a direct target of miR-548p, which functioned as a tumor suppressor in breast cancer. Moreover, miR-548p overexpression was able to reverse the circKDM4C-induced attenuation of malignant phenotypes and elevated expression of PBLD in breast cancer cells. Taken together, our data indicate that circKDM4C might have considerable potential as a prognostic biomarker in breast cancer, and support the notion that therapeutic targeting of circKDM4C/miR-548p/PBLD axis may be a promising treatment approach for breast cancer patients.

Tamoxifen is the most commonly used endocrine therapy for patients with hormone receptor (HR)-positive breast cancer. Despite its initial therapeutic efficacy, many patients eventually develop drug resistance, which remains a serious clinical challenge. To investigate roles of circular RNAs (circRNAs) in tamoxifen resistance, a tamoxifen-resistant MCF-7 cell line was established and screened for its circRNA expression profile by RNA sequencing. hsa_circ_0025202, a circRNA that was significantly downregulated, was selected for further investigation. Using a large cohort of clinical specimens, we found that hsa_circ_0025202 exhibited low expression in cancer tissues and was negatively correlated with lymphatic metastasis and histological grade. Gain- and loss-of-function assays indicated that hsa_circ_0025202 could inhibit cell proliferation, colony formation, and migration and increase cell apoptosis and sensitivity to tamoxifen. Bioinformatics and luciferase reporter assays verified that hsa_circ_0025202 could act as a miRNA sponge for miR-182-5p and further regulate the expression and activity of FOXO3a. Functional studies revealed that tumor inhibition and tamoxifen sensitization effects of hsa_circ_0025202 were achieved via the miR-182-5p/FOXO3a axis. Moreover, in vivo experiments confirmed that hsa_circ_0025202 could suppress tumor growth and enhance tamoxifen efficacy. Taken together, hsa_circ_0025202 served an anti-oncogenic role in HR-positive breast cancer, and it could be exploited as a novel marker for tamoxifen-resistant breast cancer.

Triple-negative breast cancer (TNBC) is highly heterogeneous and has a poor prognosis. It is therefore important to identify the underlying molecular mechanisms in order to develop novel therapeutic strategies. Although emerging research has revealed long noncoding RNAs (lncRNA) as vital to carcinogenesis and cancer progression, their functional involvement in TNBC has not been well defined. In this study, we utilized the The Cancer Genome Atlas (TCGA) database and analyzed clinical samples to show that the long noncoding antisense transcript of nicotinamide phosphoribosyltransferase (NAMPT), NAMPT-AS, is upregulated in TNBC and is associated with poor prognosis, lymph node involvement, metastasis, and advanced stage. NAMPT-AS was cotranscribed with NAMPT from a bidirectional promoter, where the distributions of H3K4me3 and H3K27Ac chromatin modifications were enriched based on ENCODE and FANTOM5, suggesting the potential enhancer-RNA characteristics of NAMPT-AS. NAMPT-AS epigenetically regulated the expression of NAMPT in two divergent ways: NAMPT-AS recruited POU2F2 to activate the transcription of NAMPT, and NAMPT-AS acted as a competing endogenous RNA to rescue NAMPT degradation from miR-548b-3p. NAMPT-AS/NAMPT promoted tumor progression and regulated autophagy through the mTOR pathway

Recent studies have shown that long non-coding RNAs (lncRNAs) are involved in a number of biological processes; however, further study is still warranted to comprehensively reveal their functions. In this study, we showed that the lncRNA in non-homologous end joining (NHEJ) pathway 1 (LINP1) was related to breast cancer cell proliferation, metastasis and chemoresistance. Loss- and gain-of function studies were used to assess the role of LINP1 in promoting breast cancer progression. LINP1 knockdown mitigated breast cancer cell growth by inducing G1-phase cell cycle arrest and apoptosis. LINP1 also promoted breast cancer cell metastasis and influenced the expression of epithelial-mesenchymal transition-related markers. We identified p53 as a regulator of LINP1, and LINP1 overexpression could restore the metastatic effects of p53. Furthermore, LINP1 was upregulated in doxorubicin- and 5-fluorouracil-resistant cells and induced chemoresistance. We also observed that LINP1 enrichment played a critical functional role in chemoresistance by inhibiting chemotherapeutics-induced apoptosis. Moreover, LINP1 in tumors was associated with lower overall survival and disease-free survival. In conclusion, LINP1 may serve as a potential oncogene and chemoresistance-related regulator of breast cancer cells, suggesting that LINP1 might be a potent therapeutic target and might reduce chemoresistance in breast cancer.

Chemo-resistance and metastasis of triple negative breast cancer (TNBC) contributed the most of treatment failure in the clinic. MicroRNAs (miRNAs) have been proved to be involved in many biological processes and diseases. In this study, we aimed to determine the role of miR-770 in the regulation of chemo-resistance and metastasis of TNBC. Clinically, miR-770 was highly expressed in chemo-sensitive tissues and predicted a better prognosis of TNBC. Functionally, ectopic expression of miR-770 suppressed the doxorubicin-resistance of TNBC cell lines via regulation of apoptosis and tumor microenvironment, which was mediated by exosomes. Moreover, miR-770 overexpression inhibited the migration and invasion. Rescue of STMN1 could partly reverse the effect of miR-770 in TNBC behaviors. Furthermore, we also demonstrated that overexpression of miR-770 inhibited DOX resistance and metastasis in vivo. Taken together, our results proved that miR-770 could suppress the doxorubicin-resistance and metastasis of TNBC cells, which broaden our insights into the underlying mechanisms in chemo-resistance and metastasis, and provided a new prognostic marker for TNBC cells.