Young age is associated with inferior outcomes in early-stage luminal B breast cancer patients who undergo mastectomy.

Aim: This retrospective study aimed to evaluate the effect of age on cancer relapse and survival in breast cancer patients undergoing different treatments. Methods: The propensity score method was used to correct for disparities between two groups; 2049 young patients were matched to 4053 older patients. Kaplan-Meier curves and Cox proportional hazards models were used to assess disease-free survival. Results: In the original cohort, young patients showed higher lymph node metastasis, hormone-receptor positivity and high Ki-67 levels. After propensity score matching, the disease-free survival of young patients with the luminal B-like subtype who received mastectomy with early stage disease exhibited inferior survival. Conclusion: Decisions about biology-driven systemic treatment strategies for young patients are worthy of discussion with a multidisciplinary tumor board.

LINC00478-derived novel cytoplasmic lncRNA LacRNA stabilizes PHB2 and suppresses breast cancer metastasis via repressing MYC targets.

BACKGROUND: Metastasis is the predominant cause of mortality in patients with breast cancer. Long noncoding RNAs (lncRNAs) have been shown to drive important phenotypes in tumors, including invasion and metastasis. However, the lncRNAs involved in metastasis and their molecular and cellular mechanisms are still largely unknown. METHODS: The transcriptional and posttranscriptional processing of LINC00478-associated cytoplasmic RNA (LacRNA) was determined by RT-qPCR, semiquantitative PCR and 5'/3' RACE. Paired-guide CRISPR/cas9 and CRISPR/dead-Cas9 systems was used to knock out or activate the expression of LacRNA. Cell migration and invasion assay was performed to confirm the phenotype of LacRNA. Tail vein model and mammary fat pad model were used for in vivo study. The LacRNA-PHB2-cMyc axis were screened and validated by RNA pulldown, mass spectrometry, RNA immunoprecipitation and RNA-seq assays. RESULTS: Here, we identified a novel cytoplasmic lncRNA, LacRNA (LINC00478-associated cytoplasmic RNA), derived from nucleus-located lncRNA LINC00478. The nascent transcript of LINC00478 full-length (LINC00478_FL) was cleaved and polyadenylated, simultaneously yielding 5' ends stable expressing LacRNA, which is released into the cytoplasm, and long 3' ends of nuclear-retained lncRNA. LINC00478_3'RNA was rapidly degraded. LacRNA significantly inhibited breast cancer invasion and metastasis in vitro and in vivo. Mechanistically, LacRNA physically interacted with the PHB domain of PHB2 through its 61-140-nt region. This specific binding affected the formation of the autophagy degradation complex of PHB2 and LC3, delaying the degradation of the PHB2 protein. Unexpectedly, LacRNA specifically interacted with PHB2, recruited c-Myc and promoted c-Myc ubiquitination and degradation. The negatively regulation of Myc signaling ultimately inhibited breast cancer metastasis. Furthermore, LacRNA and LacRNA-mediated c-Myc signaling downregulation are significantly associated with good clinical outcomes, take advantage of these factors we constructed a prognostic predict model. CONCLUSION: Therefore, our findings propose LacRNA as a potential prognostic biomarker and a new therapeutic strategy.

MNX1 Promotes Anti-HER2 Therapy Sensitivity via Transcriptional Regulation of CD-M6PR in HER2-Positive Breast Cancer.

Although targeted therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancer has significantly prolonged survival time and improved patients' quality of life, drug resistance has gradually emerged. This study explored the mechanisms underlying the effect of the motor neuron and pancreatic homeobox 1 (MNX1) genes on drug sensitivity in HER2-positive breast cancer. From July 2017 to 2018, core needle biopsies of HER2-positive breast cancer were collected from patients who received paclitaxel, carboplatin, and trastuzumab neoadjuvant therapy at our center. Based on treatment efficacy, 81 patients were divided into pathological complete response (pCR) and non-pCR groups. High-throughput RNA sequencing results were analyzed along with the GSE181574 dataset. MNX1 was significantly upregulated in the pCR group compared with the non-pCR group in both sequencing datasets, suggesting that MNX1 might be correlated with drug sensitivity in HER2-positive breast cancer. Meanwhile, tissue array results revealed that high MNX1 expression corresponded to a good prognosis. In vitro functional tests showed that upregulation of MNX1 significantly increased the sensitivity of HER2-positive breast cancer cells to lapatinib and pyrotinib. In conclusion, MNX1 may serve as a prognostic marker for patients with HER2-positive breast cancer, and its expression may facilitate clinical screening of patients sensitive to anti-HER2-targeted therapy.

Stabilization of CCDC102B by Loss of RACK1 Through the CMA Pathway Promotes Breast Cancer Metastasis via Activation of the NF-κB Pathway.

Background: Breast cancer is one of the leading causes of cancer-related death among women, and the pathological status of axillary lymph nodes is an important predictor of prognosis. However, the mechanism involved in this early stage of metastasis remains largely unknown. Methods: Microarray analysis was used to carry out differential genomics analyses between matched pairs of metastatic sentinel lymph node tissues and breast primary tumors. The CRISPR/Cas9 gene editing system was used for in vivo screening by transplanting a loss-of-function cell pool into immunocompromised mice. MAGeCK was used to analyze the screening results. Survival analysis was performed via the Kaplan-Meier method. Cell proliferation, wound healing, migration and invasion assays were performed to confirm the phenotype. A tail vein model and subcutaneous xenotransplanted tumor model were used for the in vivo study. The relationship between coiled-coil domain containing 102B (CCDC102B) and receptor for activated C kinase 1 (RACK1) was examined using coimmunoprecipitation, mass spectrometry, nuclear protein extraction and immunofluorescence assays. The primary biological functions and pathways related to CCDC102B were enriched by RNA sequencing. Results: We identified CCDC102B through screening and found that it was significantly upregulated in metastatic lesions in lymph nodes compared to matched primary tumors. Increased expression of CCDC102B promoted breast cancer metastasis in vitro and in vivo. Additionally, high expression of CCDC102B was correlated with poor clinical outcomes in breast cancer patients. We further identified that CCDC102B was stabilized by the loss of RACK1, a protein negatively correlated with breast cancer metastasis. Mechanistically, we found that RACK1 promoted CCDC102B lysosomal degradation by mediating chaperone-mediated autophagy (CMA). The aggressive behavior of CCDC102B in breast cancer cells could be reversed by the expression of RACK1. Moreover, CCDC102B was correlated with the significant enrichment of NF-κB pathway components. Overexpressing CCDC102B led to less interaction between RACK1 and IKKa. Thus, CCDC102B positively regulates the NF-κB pathway by interacting with RACK1. Conclusion: Taken together, our findings uncover a novel role of CCDC102B in breast cancer metastasis. CCDC102B serves as a potential metastasis promoter by regulating the activation of the NF-κB pathway and can be degraded by RACK1 via CMA.

Plasma extracellular vesicle long RNA profiles in the diagnosis and prediction of treatment response for breast cancer.

A large number RNAs are enriched and stable in extracellular vesicles (EVs), and they can reflect their tissue origins and are suitable as liquid biopsy markers for cancer diagnosis and treatment efficacy prediction. In this study, we used extracellular vesicle long RNA (exLR) sequencing to characterize the plasma-derived exLRs from 112 breast cancer patients, 19 benign patients and 41 healthy participants. The different exLRs profiling was found between the breast cancer and non-cancer groups. Thus, we constructed a breast cancer diagnostic signature which showed high accuracy with an area under the curve (AUC) of 0.960 in the training cohort and 0.900 in the validation cohort. The signature was able to identify early stage BC (I/II) with an AUC of 0.940. Integrating the signature with breast imaging could increase the diagnosis accuracy for breast cancer patients. Moreover, we enrolled 58 patients who received neoadjuvant treatment and identified an exLR (exMSMO1), which could distinguish pathological complete response (pCR) patients from non-pCR with an AUC of 0.790. Silencing MSMO1 could significantly enhance the sensitivity of MDA-MB-231 cells to paclitaxel and doxorubicin through modulating mTORC1 signaling pathway. This study demonstrated the value of exLR profiling to provide potential biomarkers for early detection and treatment efficacy prediction of breast cancer.

Clinical and Genetic Predictive Models for the Prediction of Pathological Complete Response to Optimize the Effectiveness for Trastuzumab Based Chemotherapy.

BACKGROUND: Trastuzumab shows excellent benefits for HER2+ breast cancer patients, although 20% treated remain unresponsive. We conducted a retrospective cohort study to optimize neoadjuvant chemotherapy and trastuzumab treatment in HER2+ breast cancer patients. METHODS: Six hundred patients were analyzed to identify clinical characteristics of those not achieving a pathological complete response (pCR) to develop a clinical predictive model. Available RNA sequence data was also reviewed to develop a genetic model for pCR. RESULTS: The pCR rate was 39.8% and pCR was associated with superior disease free survival and overall survival. ER negativity and PR negativity, higher HER2 IHC scores, higher Ki-67, and trastuzumab use were associated with improved pCR. Weekly paclitaxel and carboplatin had the highest pCR rate (46.70%) and the anthracycline+taxanes regimen had the lowest rate (11.11%). Four published GEO datasets were analyzed and a 10-gene model and immune signature for pCR were developed. Non-pCR patients were ER+PR+ and had a lower immune signature and gene model score. Hormone receptor status and immune signatures were independent predictive factors of pCR. CONCLUSION: Hormone receptor status and a 10-gene model could predict pCR independently and may be applied for patient selection and drug effectiveness optimization.

The role of amplified in breast cancer 1 in breast cancer: A meta-analysis.

PURPOSE: Amplified in breast cancer 1 (AIB1) expression is known to be involved in the initiation and progression of malignant breast cancer (BC), but its prognostic role remains uncertain. This meta-analysis assessed reported studies to evaluate this relationship. METHODS: Electronic databases were systematically reviewed to collect eligible studies using pre-established criteria. Hazard ratios (HRs) or odds ratios (ORs) and 95% confidence intervals (CIs) were pooled to estimate the impact of AIB1 protein expression on overall survival (OS) and clinicopathologic properties of BC cases. RESULTS: Nine eligible studies, including 6774 patients, were finally assessed by the current clinical meta-analysis. AIB1 positivity correlated with reduced OS (pooled HR = 1.409, 95% CI 1.159-1.714, P = .001). AIB1 overexpression also impacted prognosis as shown by univariate (pooled HR = 1.420, 95% CI 1.154-1.747, P = .001) and multivariate (pooled HR = 1.446, 95% CI 1.099-1.956; P = .009) analyses. Notably, subgroup analyses also revealed that AIB1 overexpression was associated with poor OS in some subgroups, such as ER-positive group (pooled HR = 1.511, 95% CI 1.138-2.006, P = .004), ER-positive without tamoxifen administration group (pooled HR = 2.338, 95% CI 1.489-3.627, P < .001), and premenopausal women group (pooled HR = 1.715, 95% CI 1.231-2.390, P = .001). Additionally, high AIB1 protein levels were associated with HER2 positivity (pooled OR = 0.331, 95% CI 0.245-0.448; P < .001), poorly differentiated histological grade (pooled OR = 0.377, 95% CI 0.317-0.448; P < .001), high Ki67 (pooled OR = 0.501, 95% CI 0.410-0.612; P < .001), presence of lymph node metastases (pooled OR = 0.866, 95% CI 0.752-0.997; P = .045), and absence of progesterone receptor (pooled OR = 1.447, 95% CI 1.190-1.759; P < .001). CONCLUSIONS: This analysis demonstrated that AIB1 overexpression is related to aggressive phenotypes and unfavorable clinical outcomes in BC, and might involve in tamoxifen resistance. AIB1 may be a new prognostic biomarker and therapeutic target in BC.

Comparison of prepectoral and subpectoral breast reconstruction after mastectomies: A systematic review and meta analysis.

BACKGROUND: The safety of prepectoral breast reconstruction (PBR) after mastectomies as compared to subpectoral breast reconstruction (SBR) were unclear, so we conducted a systematic review to analyze their differences. METHODS: PubMed, EMBASE, the Cochrane Library, and Web of Science databases were searched to retrieve studies that compared PBR with SBR after mastectomies. The outcomes were complications, oncological safety, patient-reported outcomes and postoperative pain. Revman software version 5.30 and stata vesion 12 was used to conduct meta-analysis where possible. RESULTS: 16 comparative studies (12 articles and four abstracts) were included. The meta analysis showed no statistical differences in overall complications, implant loss, seroma, nipple or skin flap necrosis, hematoma, reoperation, wound dehiscence, and wound-skin infection, rippling between PBR and SBR. PBR might be associated with fewer nipple or skin flap necrosis for those who received tissue expander placement, and fewer capsular contracture rates for those who received implant. PBR might be associated with better Breast Q scores and less postoperative pain without increasing the risk of local recurrence and metastatic disease. CONCLUSION: Although available evidence is limited, PBR might be as safe as subpectoral approach. Future well designed multicenter randomized controlled trial that compare postmastectomy PBR with SBR is needed.

Pigment epithelium-derived factor promotes tumor metastasis through an interaction with laminin receptor in hepatocellular carcinomas.

Pigment epithelium-derived factor (PEDF) has complex functions in tumor metastasis, but little is known about the roles of PEDF and its receptors in hepatocellular carcinoma (HCC). Here we found that high expression of PEDF is associated with shorter overall survival in HCC patients. Forced expression of PEDF enhanced HCC cell aggressive behavior in vitro and in vivo, whereas silencing PEDF expression reduced migration and invasion. Furthermore, PEDF expression led to changes in cell morphology and the expression of epithelial-mesenchymal transition (EMT)-related markers via ERK1/2 signaling pathway, including the upregulation of N-cadherin and slug, and the downregulation of E-cadherin in HCC cells. Our results further showed that PEDF could interact with laminin receptor (LR) and LR knockdown attenuated PEDF-induced migration, invasion and the change of EMT-related markers. More importantly, in clinical HCC specimens, we found that PEDF expression was correlated with subcellular localization of LR, and that high expression of PEDF and positive expression of LR predicted a poor prognosis. In conclusion, our results demonstrate a novel functional role of PEDF/LR axis in driving metastasis through ERK1/2-mediated EMT in HCC and provided a promising prognostic marker in HCC.

The suppressor of cytokine signaling 2 (SOCS2) inhibits tumor metastasis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common cause of cancer-related death worldwide, and its incidence continues to increase. However, the mechanism underlying the development and progression of HCC remains unknown. The suppressor of cytokine signaling 2 (SOCS2) is a member of the SOCS family and influences the carcinogenesis of multiple types of tumors, but the biological roles of SOCS2 in HCC remain unclear. In this study, we found that SOCS2 expression was reduced in HCC tissues compared with matched noncancerous liver tissues. Moreover, decreased SOCS2 expression was significantly associated with the presence of intrahepatic metastasis and high histological grade in HCC patients. Colony formation assays and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays demonstrated that overexpression of SOCS2 or knockdown of endogenous SOCS2 did not significantly affect cell proliferation and tumorigenicity in HCC cells in vitro and in vivo. However, SOCS2 overexpression significantly inhibited the migration and invasion of HCC cells in vitro and inhibited metastasis in vivo. Consistent with these findings, the knockdown of endogenous SOCS2 enhanced migration and invasion in HCC cells in vitro. Our study demonstrated that SOCS2 inhibited human HCC metastasis, and SOCS2 might provide a new potential therapeutic strategy for treating HCC.