Targeting RNA N6-methyladenosine modification: a precise weapon in overcoming tumor immune escape.

Immunotherapy, especially immune checkpoint inhibitors (ICIs), has revolutionized the treatment of many types of cancer, particularly advanced-stage cancers. Nevertheless, although a subset of patients experiences dramatic and long-term disease regression in response to ICIs, most patients do not benefit from these treatments. Some may even experience cancer progression. Immune escape by tumor cells may be a key reason for this low response rate. N6-methyladenosine (m6A) is the most common type of RNA methylation and has been recognized as a critical regulator of tumors and the immune system. Therefore, m6A modification and related regulators are promising targets for improving the efficacy of tumor immunotherapy. However, the association between m6A modification and tumor immune escape (TIE) has not been comprehensively summarized. Therefore, this review summarizes the existing knowledge regarding m6A modifications involved in TIE and their potential mechanisms of action. Moreover, we provide an overview of currently available agents targeting m6A regulators that have been tested for their elevated effects on TIE. This review establishes the association between m6A modifications and TIE and provides new insights and strategies for maximizing the efficacy of immunotherapy by specifically targeting m6A modifications involved in TIE.

Genome-wide cell-free DNA methylation analyses improve accuracy of non-invasive diagnostic imaging for early-stage breast cancer.

Early detection is crucial to improve breast cancer (BC) patients' outcomes and survival. Mammogram and ultrasound adopting the Breast Imaging Reporting and Data System (BI-RADS) categorization are widely used for BC early detection, while suffering high false-positive rate leading to unnecessary biopsy, especially in BI-RADS category-4 patients. Plasma cell-free DNA (cfDNA) carrying on DNA methylation information has emerged as a non-invasive approach for cancer detection. Here we present a prospective multi-center study with whole-genome bisulfite sequencing data to address the clinical utility of cfDNA methylation markers from 203 female patients with breast lesions suspected for malignancy. The cfDNA is enriched with hypo-methylated genomic regions. A practical computational framework was devised to excavate optimal cfDNA-rich DNA methylation markers, which significantly improved the early diagnosis of BI-RADS category-4 patients (AUC from 0.78-0.79 to 0.93-0.94). As a proof-of-concept study, we performed the first blood-based whole-genome DNA methylation study for detecting early-stage breast cancer from benign tumors at single-base resolution, which suggests that combining the liquid biopsy with the traditional diagnostic imaging can improve the current clinical practice, by reducing the false-positive rate and avoiding unnecessary harms.

Pertuzumab and trastuzumab as adjuvant treatment for HER2-positive early breast cancer: outcomes in Chinese patients in the APHINITY study.

BACKGROUND: The addition of pertuzumab to trastuzumab plus standard chemotherapy as adjuvant therapy following surgery significantly improved invasive disease-free survival (IDFS) in patients with HER2-positive early breast cancer in the multinational randomized APHINITY trial (NCT01358877, BIG 4-11/BO25126/TOC4939G). We analyzed clinical outcomes in the subgroup of patients recruited at Chinese sites. METHODS: Patients were randomized to standard adjuvant chemotherapy plus 1 year of trastuzumab with pertuzumab or placebo. Patients recruited in mainland China, Hong Kong and Taiwan are included in this descriptive analysis. RESULTS: Chinese patients had similar demographic characteristics to the global population, but a higher proportion had nodal involvement. Although this subgroup analysis was not powered to detect statistical significance, a numerical improvement in IDFS was observed with the addition of pertuzumab to trastuzumab in Chinese patients (hazard ratio, 0.69; 95% confidence interval: 0.39-1.19; 3-year IDFS event-free estimates 92.5% [pertuzumab] and 91.7% [placebo]), which was consistent with the primary analysis of the global population. Further subgroup analyses showed numerical improvements in the Chinese node-positive, hormone receptor-negative and -positive subgroups, although confidence intervals were wide due to the low number of events. The incidence of diarrhea was higher in the pertuzumab arm, and no primary cardiac events occurred in Chinese patients in either arm. CONCLUSIONS: Pertuzumab, used in combination with trastuzumab and chemotherapy in APHINITY, is effective as an adjuvant treatment regimen for Chinese patients with HER2-positive early breast cancer in a setting with curative intent. The safety profile in Chinese patients was consistent with that of the global population.

Long noncoding RNA PVT1 acts as an oncogenic driver in human pan-cancer.

Increasing evidence indicates that long noncoding RNAs (lncRNAs) play pivotal roles during tumorigenesis in multiple types of cancers. However, little is known about the exact role of plasmacytoma variant translocation 1 (PVT1) in human pan-cancer. Here, we report the oncogenic role and function of PVT1 in human pan-cancer, including breast cancer. The expression of PVT1 in human tumor tissues and nontumor tissues, the upstream regulation of PVT1 and the relationship between its expression and prognosis and chemoresistance were examined by using The Cancer Genome Atlas data. PVT1 expression is higher in human cancer tissues compared with adjacent noncancerous tissues, and patients with high levels of PVT1 expression usually have tumors with a higher TNM stage. High PVT1 expression is also associated with worse disease outcomes in patients with cancer. Hypomethylation and transcription factor binding in the PVT1 promoter locus activates its transcriptional expression. Guilt by association analysis revealed that PVT1 may be involved in processes associated with tumorigenesis. Moreover, PVT1 may trigger chemoresistance in human cancer. These results indicated that PVT1 may act as an oncogenic driver and maybe a potential therapeutic target in human cancer.

Long noncoding RNA FER1L4 acts as an oncogenic driver in human pan-cancer.

The function of Fer-1 like family member 4 (FER1L4) in human pan-cancer is unknown. Expression of FER1L4 in tumor tissues and nontumor tissues, upstream regulation of FER1L4, and the relationship between its expression with prognosis and chemoresistance were examined by The Cancer Genome Atlas and Gene Expression Omnibus databases. Next, these results were validated in breast tumor and paired nontumor tissues in our cohort. FER1L4 expression is higher in tumor tissues compared with the adjacent nontumor tissues. High FER1L4 expression is associated with worse disease outcomes. Hypomethylation and H3K4me3 accumulation in FER1L4 promoter locus activate its transcriptional expression. Moreover, FER1L4 may trigger chemoresistance in human cancer. Gene Ontology enrichment analysis revealed that FER1L4 may be involved in processes associated with tumorigenesis. These results indicated that FER1L4 may act as an oncogenic driver and it may be a potential therapy target in human cancer.

Methylation of WT1, CA10 in peripheral blood leukocyte is associated with breast cancer risk: a case-control study.

BACKGROUND: Studies have shown that abnormal changes of specific-gene DNA methylation in leukocytes may be associated with an elevated risk of cancer. However, associations between the methylation of the zinc-related genes, WT1 and CA10, and breast cancer risk remain unknown. METHODS: The methylation of WT1 and CA10 was analyzed by methylation-sensitive high-resolution-melting (MS-HRM) in a case-control study with female subjects (N = 959). Logistic regression was used to analyze the associations, and propensity score (PS) method was used to adjust confounders. RESULTS: The results showed that WT1 hypermethylation was associated with an increased risk of breast cancer, with an odds ratio (OR) of 3.07 [95% confidence interval (CI): 1.67-5.64, P < 0.01]. Subgroup analyses showed that WT1 hypermethylation was specifically associated with an elevated risk of luminal A subtype (OR = 2.62, 95% CI: 1.11-6.20, P = 0.03) and luminal B subtype (OR = 3.23, 95% CI: 1.34-7.80, P = 0.01). CA10 hypermethylation was associated with an increased risk of luminal B subtype (OR = 1.80, 95% CI: 1.09-2.98, P = 0.02). CONCLUSION: The results of the present study suggest that the hypermethylation of WT1 methylation in leukocytes is significantly associated with an increased risk of breast cancer. The hypermethylation of WT1 is associated with an increased risk of luminal subtypes of breast cancer, and the hypermethylation of CA10 is associated with an increased risk of luminal B subtype of breast cancer.

Modulation of autophagy in human diseases strategies to foster strengths and circumvent weaknesses.

Autophagy is central to the maintenance of intracellular homeostasis across species. Accordingly, autophagy disorders are linked to a variety of diseases from the embryonic stage until death, and the role of autophagy as a therapeutic target has been widely recognized. However, autophagy-associated therapy for human diseases is still in its infancy and is supported by limited evidence. In this review, we summarize the landscape of autophagy-associated diseases and current autophagy modulators. Furthermore, we investigate the existing autophagy-associated clinical trials, analyze the obstacles that limit their progress, offer tactics that may allow barriers to be overcome along the way and then discuss the therapeutic potential of autophagy modulators in clinical applications.

Ai-lncRNA EGOT enhancing autophagy sensitizes paclitaxel cytotoxicity via upregulation of ITPR1 expression by RNA-RNA and RNA-protein interactions in human cancer.

BACKGROUND: The biology function of antisense intronic long noncoding RNA (Ai-lncRNA) is still unknown. Meanwhile, cancer patients with paclitaxel resistance have limited therapeutic options in the clinic. However, the potential involvement of Ai-lncRNA in paclitaxel sensitivity remains unclear in human cancer. METHODS: Whole transcriptome sequencing of 33 breast specimens was performed to identify Ai-lncRNA EGOT. Next, the role of EGOT in regulation of paclitaxel sensitivity was investigated. Moreover, the mechanism of EGOT enhancing autophagy sensitizes paclitaxel cytotoxicity via upregulation of ITPR1 expression by RNA-RNA and RNA-protein interactions was investigated in detail. Furthermore, upstream transcriptional regulation of EGOT expression was also investigated by co-immunoprecipitation and chromatin immunoprecipitation. Finally, clinical breast specimens in our cohort, TCGA and ICGC were applied to validate the role of EGOT in enhancing of paclitaxel sensitivity. RESULTS: EGOT enhances autophagosome accumulation via the up-regulation of ITPR1 expression, thereby sensitizing cells to paclitaxel toxicity. Mechanistically, on one hand, EGOT upregulates ITPR1 levels via formation of a pre-ITPR1/EGOT dsRNA that induces pre-ITPR1 accumulation to increase ITPR1 protein expression in cis. On the other hand, EGOT recruits hnRNPH1 to enhance the alternative splicing of pre-ITPR1 in trans via two binding motifs in EGOT segment 2 (324-645 nucleotides) in exon 1. Moreover, EGOT is transcriptionally regulated by stress conditions. Finally, EGOT expression enhances paclitaxel sensitivity via assessment of cancer specimens. CONCLUSIONS: These findings broaden comprehensive understanding of the biology function of Ai-lncRNAs. Proper regulation of EGOT may be a novel synergistic strategy for enhancing paclitaxel sensitivity in cancer therapy.

Effects of FGFR1 Gene Polymorphisms on the Risk of Breast Cancer and FGFR1 Protein Expression.

BACKGROUND/AIMS: Fibroblast growth factor receptor 1 (FGFR1) is widely considered to play an important role in mammary carcinogenesis. Some common variants in FGFR1 might be associated with its expression, and further affect breast cancer risk. The aim of this study was to investigate effects of single-nucleotide polymorphisms (SNPs) in FGFR1 on breast cancer susceptibility and FGFR1 protein expression. METHODS: SNPs rs17182023, rs17175624 and rs10958704 in FGFR1 were genotyped in 747 breast cancer cases and 716 healthy controls by SNaPshot method. The associations between SNPs and breast cancer were examined by logistic regression. Immunohistochemistry(IHC) was used to detect FGFR1 protein expression, and the association of FGFR1 polymorphisms with its protein expression was analyzed by Pearson's chi-square test. Additionally, Cox regression and Kaplan-Meier analysis was used to evaluate the association between FGFR1 protein expression and breast cancer prognosis. RESULTS: The minor allele of rs17182023 in FGFR1 was significantly associated with reduced breast cancer risk, with an odds ratio of 0.800 (95%CI = 0.684-0.935). No significant associations were detected between other SNPs and breast cancer. Moreover, rs17182023 was correlated to FGFR1 protein expression (P = 0.006), and patients with high FGFR1 protein expression tended to have poor outcomes. CONCLUSIONS: SNP rs17182023 was correlated to reduced breast cancer risk, and was associated with FGFR1 protein expression. High FGFR1 protein expression was an independent risk factor of breast cancer, and resulted in poor prognosis.

HOXD3 Plays a Critical Role in Breast Cancer Stemness and Drug Resistance.

BACKGROUND/AIMS: Homeobox D3 (HOXD3) is a member of the homeobox family of genes that is known primarily for its transcriptional regulation of morphogenesis in all multicellular organisms. In this study, we sought to explore the role that HOXD3 plays in the stem-like capacity, or stemness, and drug resistance of breast cancer cells. METHODS: Expression of HOXD3 in clinical breast samples were examined by RT-PCR and immunohistochemistry. HOXD3 expression in breast cancer cell lines were analyzed by RT-PCR and western blot. Ability of drug resistance in breast cancer cells were elevated by MTT cell viability and colony formation assays. We examined stemness using cell fluorescent staining, RT-PCR and western blot for stem cell marker expression. Finally, activity of wnt signaling was analyzed by FOPflash luciferase assays. RT-PCR and western blot were performed for downstream genes of wnt signaling. RESULTS: We demonstrated that HOXD3 is overexpressed in breast cancer tissue as compared to normal breast tissue. HOXD3 overexpression enhances breast cancer cell drug resistance. Furthermore, HOXD3 upregulation in the same cell lines increased sphere formation as well as the expression levels of stem cell biomarkers, suggesting that HOXD3 does indeed increase breast cancer cell stemness. Because we had previously shown that HOXD3 expression is closely associated with integrin ß3 expression in breast cancer patients, we hypothesized that HOXD3 may regulate breast cancer cell stemness and drug resistance through integrin ß 3. Cell viability assays showed that integrin ß 3 knockdown increased cell viability and that HOXD3 could not restore cancer cell stemness or drug resistance. Given integrin ß 3's relationship with Wnt/ß-catenin signaling, we determine whether HOXD3 regulates integrin ß 3 activity through Wnt/ß-catenin signaling. We found that, even though HOXD3 increased the expression of Wnt/ß-catenin downstream genes, it did not restore Wnt/ß-catenin signaling activity, which was inhibited in integrin ß3 knockdown breast cancer cells. CONCLUSION: We demonstrate that HOXD3 plays a critical role in breast cancer stemness and drug resistance via integrin ß3-mediated Wnt/ß-catenin signaling. Our findings open the possibility for improving the current standard of care for breast cancer patients by designing targeted molecular therapies that overcome the barriers of cancer cell stemness and drug resistance.

Hypoxia-Induced TPM2 Methylation is Associated with Chemoresistance and Poor Prognosis in Breast Cancer.

BACKGROUND/AIMS: Tropomyosin-2 (TPM2) plays important roles in functions of the cytoskeleton, such as cytokinesis, vesicle transport, cell proliferation, migration and apoptosis,and these functions imply that TPM2 also plays a role in cancer development. Indeed, it has been shown that TPM2 plays a critical role in some cancers. However, the role of TPM2 in breast cancer is still poorly characterized. Thus, we explored the role of TPM2 in breast cancer. METHODS: We analysed TPM2 expression and its correlation with the clinicopathological features in breast cancer. Then, we examined the influence of hypoxia on TPM2 expression and methylation status using bisulfite sequencing PCR. Furthermore, we performed TPM2-mediated migration and invasion assays in the context of hypoxia and examined changes in matrix metalloproteinase-2 (MMP2) expression. Finally, we detected the influence of TPM2 on survival and chemotherapy drug sensitivity. RESULTS: We found that TPM2 expression is down-regulated in breast cancer cells compared to that in normal breast cells. The data from TCGA supported these results. Promoter methylation of TPM2, which could be induced by hypoxia, was responsible for its low expression. Hypoxia might regulate cell invasiveness partly by TPM2 down-regulation-mediated changes of MMP2 expression. Importantly, low TPM2 expression was correlated with lymph node metastasis (P=0.031), tumour node metastasis stage (P=0.01), histological grade (P=0.037), and shorter overall survival (P=0.028). Univariate and multivariate analyses indicated that TPM2 was an independent predictor in breast cancer patients. Paclitaxel chemotherapy did not benefit patients with low TPM2 expression (P<0.0001). TPM2 knockdown significantly reduced cell sensitivity to paclitaxel. CONCLUSION: TPM2 is a potential novel tumour suppressor gene in breast cancer. TPM2 is associated with poor survival and chemoresistance to paclitaxel in breast cancer, and TPM2 may represent a promising therapeutic gene target for breast cancer patients with chemoresistance.

Prognostic implications of fibroblast growth factor receptor 4 polymorphisms in primary breast cancer.

Fibroblast growth factor receptor 4 (FGFR4) belongs to the receptor tyrosine kinase (RTK) family, and FGFR4 polymorphisms have been implicated in both normal development and cancer, including breast cancer. In the present study, we investigated correlations between polymorphisms in FGFR4 and breast cancer prognosis. The FGFR4 SNPs rs1966265 and rs351855 were genotyped in 747 breast cancer patients using the SNaPshot method. FGFR4 protein expression was detected by immunohistochemistry in 339 samples. SNP rs351855 was correlated with FGFR4 protein expression under dominant and co-dominant models. Lymph node metastasis (LNM), ER (estrogen receptor) status, and molecular subtype were associated with high FGFR4 expression. Univariate analysis revealed rs351855 (CC/CT: P = 0.027, CC/TT: P < 0.001, CC/CT + TT: P = 0.005) to be a prognostic predictor, and multivariate analysis indicated rs351855 (CC/TT: P = 0.005) to be an independent prognostic factor. Kaplan-Meier survival analysis showed that high FGFR4 protein expression was associated with a poor prognosis. SNP rs351855 was correlated with worse outcomes, with a dose-dependent effect. The results of this study show that FGFR4 SNP rs351855 is associated with up-regulation of FGFR4 protein expression and a worse prognosis in breast cancer.

Oncogenic long noncoding RNA landscape in breast cancer.

BACKGROUND: Few long noncoding RNAs (lncRNAs) that act as oncogenic genes in breast cancer have been identified. METHODS: Oncogenic lncRNAs associated with tumourigenesis and worse survival outcomes were examined and validated in Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA), respectively. Then, the potential biological functions and expression regulation of these lncRNAs were studied via bioinformatics and genome data analysis. Moreover, progressive breast cancer subtype-specific lncRNAs were investigated via high-throughput sequencing in our cohort and TCGA validation. To elucidate the mechanisms of the regulation of these lncRNAs, genomic alterations from the TCGA, Broad, Sanger and BCCRC data, as well as epigenetic modifications from GEO data, were then applied and examined to meet this objective. Finally, cell proliferation assays, flow cytometry analyses and TUNEL assays were applied to validate the oncogenic roles of these lncRNAs in vitro. RESULTS: A cluster of oncogenic lncRNAs that was upregulated in breast cancer tissue and was associated with worse survival outcomes was identified. These oncogenic lncRNAs are involved in regulating immune system activation and the TGF-beta and Jak-STAT signalling pathways. Moreover, TINCR, LINC00511, and PPP1R26-AS1 were identified as subtype-specific lncRNAs associated with HER-2, triple-negative and luminal B subtypes of breast cancer, respectively. The up-regulation of these oncogenic lncRNAs is mainly caused by gene amplification in the genome in breast cancer and other solid tumours. Finally, the knockdown of TINCR, DSCAM-AS1 or HOTAIR inhibited breast cancer cell proliferation, increased apoptosis and inhibited cell cycle progression in vitro. CONCLUSIONS: These findings enhance the landscape of known oncogenic lncRNAs in breast cancer and provide insights into their roles. This understanding may potentially aid in the comprehensive management of breast cancer.

Long Noncoding RNA Linc00152 Functions as a Tumor Propellant in Pan-Cancer.

BACKGROUND/AIMS: The oncogenic role of linc00152 in pan-cancer is unclear. METHODS: In this study, RNA-Seq of 33 breast specimens was performed, and the expression of linc00152 was validated by qPCR using 50 paired breast cancer tissues and adjacent normal tissues. This result combined with the expression of linc00152 in pan-cancer was revalidated by Gene Expression Omnibus and The Cancer Genome Atlas data. Next, the oncogenic roles of linc00152 in view of prognosis, chemoresistance, genomic and epigenetic regulation, including DNA methylation and histone modification, potential biological function enrichment, and basic molecular function in pan-cancer, were also evaluated in vitro and in vivo. RESULTS: Linc00152 is upregulated in pan-cancer, especially in progressive cancer, and the high expression of linc00152 may lead to a worse prognosis and chemoresistance in pan-cancer patients. Amplification, DNA hypomethylation, promoter-like lncRNA characteristics and super-enhancer regulation are the drivers that lead to the upregulation of linc00152 in pan-cancer. Meanwhile, linc00152 was involved in cancer-related pathways, infection and immune response-associated pathways by enriched analysis using TCGA data. Finally, linc00152 was confirmed to promote the proliferation, migration and invasion in MDA-MB-231, SGC-7901 and 786-O. Moreover, RIP and RNA pull-down assays indicated that linc00152 can bind to EZH2 directly. CONCLUSION: All of the results indicated that linc00152 acted as an oncogenic propellant from various perspectives, and it may be an effective therapy target in pan-cancer.

Development of a Novel Transparent Flexible Capacitive Micromachined Ultrasonic Transducer.

This paper presents the world's first transparent flexible capacitive micromachined ultrasonic transducer (CMUT) that was fabricated through a roll-lamination technique. This polymer-based CMUT has advantages of transparency, flexibility, and non-contacting detection which provide unique functions in display panel applications. Comprising an indium tin oxide-polyethylene terephthalate (ITO-PET) substrate, SU-8 sidewall and vibrating membranes, and silver nanowire transparent electrode, the transducer has visible-light transmittance exceeding 80% and can operate on curved surfaces with a 40 mm radius of curvature. Unlike the traditional silicon-based high temperature process, the CMUT can be fabricated on a flexible substrate at a temperature below 100 °C to reduce residual stress introduced at high temperature. The CMUT on the curved surfaces can detect a flat target and finger at distances up to 50 mm and 40 mm, respectively. The transparent flexible CMUT provides a better human-machine interface than existing touch panels because it can be integrated with a display panel for non-contacting control in a health conscious environment and the flexible feature is critical for curved display and wearable electronics.

Fully human monoclonal antibodies to TRAIL-R1 enhance TRAIL-induced apoptosis via activation of caspase-8 pathway.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or agonistic antibodies targeting TRAIL-receptors (TRAIL-Rs) can selectively induce apoptosis in cancer cells. However, they have limited antitumor efficacy in clinical trials. We previously generated ten fully human monoclonal Abs to TRAIL-receptor type 1 (TR1-mAbs) using immunospot array assay on a chip (ISAAC technology). We found that the TR1-mAbs exhibited different effects on TRAIL-induced apoptosis (enhanced or blocked apoptosis). Here, we further demonstrated that some mAbs competed with TRAIL for binding to TRAIL-R1 expressed on tumor cells that blocked TRAIL-induced apoptosis (B-TR1-Ab), whereas others did not compete with TRAIL that enhanced TRAIL-induced apoptosis (E-TR1-Ab). Combination of E-TR1-Ab (TR1-419) with TRAIL leads to enhanced antitumor activity in various tumor cells in vitro. E-TR1-419 and TRAIL could cooperate to upregulate the mRNA expression and protein levels of TRAIL-R1 and to promote caspase-8 cleavage and increased JNK phosphorylation. Our results suggest that combining E-TR1 Ab with TRAIL could provide a new therapeutic strategy for tumor immunotherapies.

Long non-coding RNA MVIH is associated with poor prognosis and malignant biological behavior in breast cancer.

In recent years, with the development of transcriptomics, the effect of long non-coding RNAs (LncRNAs) on the regulation of biological processes is being elucidated. LncRNAs play an important role in tumor occurrence and development. LncRNA associated with microvascular invasion in hepatocellular carcinoma (LncRNA MVIH) was first identified in hepatocellular carcinoma and is associated with angiogenesis, tumor growth and metastasis upregulation, and poor recurrence-free survival. MVIH has an important role in non-small cell lung cancer, in which it promotes cell proliferation and metastasis, and high MVIH expression indicates poor overall survival. However, the involvement of MVIH in breast cancer is unclear. Our research revealed that the expression levels of MVIH in breast cancer tissues were higher than in adjacent noncancerous tissues, and high MVIH expression was correlated with Ki67 expression. Moreover, breast cancer patients with high MVIH expression levels showed poor overall survival and disease-free survival. Multivariate analysis results indicated that MVIH was an independent prognostic factor in breast cancer. In addition, upregulated MVIH expression levels promoted cell proliferation and cell cycle, and inhibited cell apoptosis, while reduced MVIH expression showed the converse. In summary, our findings suggest that MVIH may have an important role in breast cancer and may serve as a new biomarker and a potential therapeutic target.

Transcriptome sequencing of HER2-positive breast cancer stem cells identifies potential prognostic marker.

In cancer stem cell theory, breast cancer stem cells (BCSCs) are postulated to be the root cause of recurrence and metastasis in breast cancer. Discovery of new biomarkers and development of BCSC-targeted therapy are practical issues that urgently need to be addressed in the clinic. However, few breast cancer stem cell targets are known. Given that there are few BCSCs, performing transcriptome sequencing on them thus far has not been possible. With the emergence of single-cell sequencing technology, we have now undertaken such a study. We prepared single-cell suspensions, which were sorted using flow cytometry from breast tumor tissue and adjacent normal breast tissue from two HER2-positive patients. We obtained BCSCs, breast cancer cells, mammary cells, and CD44+ mammary cells. Transcriptome sequencing was then performed on these four cell types. Using bioinformatics, we identified 404 differentially expressed BCSC genes from the HER2-positive tumors and preliminary explored transcriptome characteristics of BCSCs. Finally, by querying a public database, we found that CA12 was a novel prognostic biomarker in HER2-positive breast cancer, which also had prognostic value in all breast cancer types. In conclusion, our results suggest that CA12 may be associated with BCSCs, especially HER2-positive BCSCs, and is a potential novel therapeutic target and biomarker.

Health-related quality of life of postmenopausal Chinese women with hormone receptor-positive early breast cancer during treatment with adjuvant aromatase inhibitors: a prospective, multicenter, non-interventional study.

BACKGROUND: Estimating quality of life (QoL) in patients with breast cancer is of importance in assessing treatment outcomes. Adjuvant endocrine therapy is widely used for hormone receptor-positive (HR+) early-stage breast cancer (EBC), and evidence suggests that aromatase inhibitors (AIs) may improve QoL for these patients. This study evaluated QoL in postmenopausal Chinese patients with HR+ EBC taking AIs. METHODS: This was a prospective, multicenter, and observational study that had no intent to intervene in the current treatment of recruited patients. Eligible patients were recruited within 7 days of beginning adjuvant treatment with AIs. The Functional Assessment of Cancer Therapy-Breast (FACT-B) scale was used to evaluate the patients' QoL. Data were collected at baseline and at 6, 12, 18, and 24 months. RESULTS: From June 2010 to October 2013, a total of 494 patients with HR+ EBC were recruited from 21 centers. There was a 7.51-point increase in the patients' mean FACT-B trial outcome index (TOI), from 90.69 at baseline to 98.72 at 24 months (P < .0001). The mean TOI scores at baseline, 6, 12, and 18 months were 90.69, 94.36, 97.71, and 96.75, respectively (P < .0001, for all). The mean (FACT-B) emotional well-being subscale scores at baseline, 6, 12, 18, and 24 months were 16.32, 16.55, 17.34 (P < .0001), 17.47 (P < .0001), and 17.85 (P < .0001), respectively, and social well-being scores were 18.61, 19.14 (P < .04), 19.35 (P < .008), 18.32, and 18.40, respectively. In the mixed model, baseline TOI, clinical visits, prior chemotherapies, age group, and axillary lymph-node dissection presented statistically significant effects on the change of FACT-B TOI and FACT-B SWB, whereas only baseline TOI, clinical visits, and prior chemotherapies presented statistically significant effects on the change of FACT-B EWB. FACT-B TOI, being the most pertinent and precise indicator of patient-reported QoL, demonstrated significant changes reflecting clinical benefit of adjuvant AIs endocrine therapy in the QoL of HR + EBC patients. CONCLUSIONS: The study demonstrated significant improvements in the long-term QoL of postmenopausal Chinese patients with HR+ EBC at 6, 12, 18, and 24 months after starting treatment with AIs. The current study indicates improved long-term QoL with AI adjuvant treatment, which will aid clinicians in optimizing treatment to yield effective healthcare outcomes. TRIAL REGISTRATION: Clinicaltrials.gov NCT01144572.

Decreased Wnt5a Expression is a Poor Prognostic Factor in Triple-Negative Breast Cancer.

BACKGROUND: Wingless-type MMTV integration site family member 5A (Wnt5a) has been documented to either overexpress or be lost in several malignancies. Our study aimed to investigate the expression and clinical significance of Wnt5a protein in triple-negative breast cancer (TNBC). MATERIAL/METHODS: By using immunohistochemistry, Wnt5a expression was evaluated in 90 TNBC specimens. The association between Wnt5a expression and clinic-pathological factors was assessed by using the chi-square test. The survival analysis of patients was conducted by using the Kaplan-Meier and log-rank tests. Cox regression was utilized for the univariate and multivariate analyses of prognostic factors. RESULTS: Results showed that negative Wnt5a expression correlated with positive lymph node metastasis (LNM) (P=0.007) and Ki67 proliferation (P=0.002). Patients with negative Wnt5a expression had significantly poorer recurrence-free survival (RFS) than patients with positive Wnt5a expression (P=0.008). Multivariate Cox regression analysis revealed that decreased Wnt5a expression was an independent prognostic factor for RFS (P=0.014). CONCLUSIONS: Negative Wnt5a protein expression might contribute to the tumor progression and poor prognosis of TNBC and might be a new therapy target in TNBC.