Sushi domain-containing protein 2 (SUSD2), a transmembrane protein containing a sushi motif, has been reported to have tumor-promoting functions in various types of cancer, including breast cancer. However, the regulatory mechanism of SUSD2 and its function in HER2-positive (HER2+) breast cancer have not been fully identified as yet. In this study, we explored the potential of targeting SUSD2 to overcome trastuzumab (TRZ) resistance in HER2+ breast cancer. SUSD2 expression was found to be significantly increased in HER2-overexpressing cells. Endogenous SUSD2 expression was observed in HER2+ breast cancer cells but not in estrogen receptor-positive or triple-negative breast cancer cells. We also found that SUSD2 expression was positively correlated with HER2 expression in a publicly available human primary breast cancer dataset. Although SUSD2 expression was associated with HER2, its expression levels were not affected by TRZ. Through kinase array experiments, we found that SUSD2 expression was modulated downstream of STAT3-dependent signaling in breast cancer cells overexpressing HER2. STAT3 activity was increased in EGFR+ HER2+ breast cancer cells compared to EGFR+ cells. Furthermore, we observed that SUSD2 expression was decreased by C188-9, a STAT3-specific inhibitor. Finally, we analyzed the association between patient survival and SUSD2 expression in breast cancer. Our results showed that SUSD2 expression had a negative correlation with the relapse-free survival of patients with EGFR+ HER2+ breast cancer when compared to EGFR+ breast cancer patients. Collectively, our results demonstrate that SUSD2 expression is mediated by STAT3 and imply the potential of using SUSD2 as a biomarker to stratify HER2+ breast cancer.
Abstract Background: Triple-negative breast cancer (TNBC) is highly heterogeneous cancer and the most challenging subtype of breast cancer. And its prognosis is poor compared to the other subtypes. Unlike luminal type cancers, there is no valid biomarker to predict the prognosis of patients with early TNBC. To establish an elaborate therapeutic strategy for TNBC, biomarkers that accurately predict the prognosis and response to treatment are needed. Method: 184 patients with early stage TNBC (training cohort, n = 76; validation cohort, n = 108) were enrolled. Median Follow-up period was 51.5 months (range: 4.6-230.8) for training cohort and 58.3 months (range: 6.6-99.8) for validation cohort. Of the patients in training cohort, 13 patients had recurrence or metastasis. Of the patients in validation cohort, 23 patients had recurrence or metastasis. Using a HiSeq sequencer, RNA sequencing was conducted to analyze the gene expression profiles of tumor samples from TNBC patients. Gene signature was analyzed by combination of DEGs which found in gene expression profiles. Cross validation and meta-analysis were conducted as pre-validation. Meta-analysis was conducted using CBS probePINGS. To compare gene signature and other methods, PAM 50 call and TCR diversity analysis were investigated. Statistical analyses were conducted using R language (v.3.4.3). Result: To predict prognosis of recurrence or metastasis for TNBC patients, we identified the 10-gene signature (DGKH, GADD45B, KLF7, LYST, NR6A1, PYCARD, ROBO1, SLC22A20P, SLC24A3 and SLC45A4) that stratified patients with TNBC by risk score (sensitivity = 92.31%; specificity = 92.06%; accuracy = 92.11%) and validated in a cohort of separate institutions. Meta-analysis supported the biological relevance of the 10-gene signature to well-known driving pathways in TNBC. When compared with other potential biomarkers like PAM 50 call and T-cell receptor β diversity, the 10-gene signature was the only independent factor that can predict prognosis for invasive disease-free survival in multivariate analysis. Conclusion: Our novel findings can contribute to solving the diagnostic challenges in TNBC and the 10-gene signature may serve as a novel biomarker for risk-based patient care. Citation Format: Chang Min Kim, Kyong Hwa Park, Yun Suk Yu, Ju Won Kim, Jin Young Park, Jeong Eon Lee, Sung Hoon Sim, Bo Kyoung Seo, Jin Kyeoung Kim, Eun Sook Lee, Yeon Hee Park, Sun-Young Kong. A 10-gene signature to predict the prognosis of early-stage triple-negative 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 P2-11-25.
Interleukin-1 (IL1) is a proinflammatory cytokine and promotes cancer cell proliferation and invasiveness in a diversity of cancers, such as breast and colon cancer. Here, we focused on the pharmacological effect of Entelon® (ETL) on the tumorigenesis of triple-negative breast cancer (TNBC) cells by IL1-alpha (IL1A). IL1A enhanced the cell growth and invasiveness of TNBC cells. We observed that abnormal IL1A induction is related with the poor prognosis of TNBC patients. IL1A also increased a variety of chemokines such as CCL2 and IL8. Interestingly, IL1A expression was reduced by the ETL treatment. Here, we found that ETL significantly decreased the MEK/ERK signaling pathway in TNBC cells. IL1A expression was reduced by UO126. Lastly, we studied the effect of ETL on the metastatic potential of TNBC cells. Our results showed that ETL significantly reduced the lung metastasis of TNBC cells. Our results showed that IL1A expression was regulated by the MEK/ERK- and PI3K/AKT-dependent pathway. Taken together, ETL inhibited the MEK/ERK and PI3K/AKT signaling pathway and suppressing the lung metastasis of TNBC cells through downregulation of IL1A. Therefore, we propose the possibility of ETL as an effective adjuvant for treating TNBC.
The exact mechanism regulating fibronectin (FN) expression in breast cancer cells has not been fully elucidated. In this study, we investigated the pharmacological mechanism of berberine (BBR) with respect to FN expression in triple-negative breast cancer (TNBC) cells.The clinical significance of FN mRNA expression was analyzed using the Kaplan-Meier plotter database (http://kmplot.com/breast). FN mRNA and protein expression levels were analyzed by real-time polymerase chain reaction and western blotting, respectively.Using publicly available clinical data, we observed that high FN expression was associated with poor prognosis in patients with breast cancer. FN mRNA and protein expression was increased in TNBC cells compared with non-TNBC cells. As expected, recombinant human FN significantly induced cell spreading and adhesion in MDA-MB231 TNBC cells. We also investigated the regulatory mechanism underlying FN expression. Basal levels of FN mRNA and protein expression were downregulated by a specific activator protein-1 (AP-1) inhibitor, SR11302. Interestingly, FN expression in TNBC cells was dose-dependently decreased by BBR treatment. The level of c-Jun phosphorylation was also decreased by BBR treatment.Our findings demonstrate that FN expression is regulated via an AP-1-dependent mechanism, and that BBR suppresses FN expression in TNBC cells through inhibition of AP-1 activity.
Abstract Background: Immediate breast reconstruction with tissue expander in patients who were expected to receive adjuvant therapy, such as chemotherapy or radiotherapy, has been a topic of debate. Postoperative complications from tissue expander procedures can delay the timing of adjuvant treatment and subsequently increase the probability of recurrence. The purpose of this study was to identify the impact of chemotherapy and radiotherapy on postoperative complications in patients who underwent immediate reconstruction (IR) using tissue expander. Methods: We conducted a retrospective study of 1,081 breast cancer patients who underwent mastectomy and IR using tissue expander insertion between 2012 and 2017 in Samsung Medical Center. The patients were divided into two groups based on complications (complication group vs. no complication group). Complication group was regarded to have surgical removal or conservative treatment based on clinical findings such as infection, capsular contracture, seroma, hematoma, rupture, malposition, tissue viability, or cosmetic problem. The complication group had 59 patients (5.5%) and the no complication group had 1,022 patients (94.5%). Results: In univariate analysis, adjuvant radiotherapy and adjuvant chemotherapy were significantly associated with postoperative complications. In multivariate analysis, however, only higher pathologic N stage was significantly associated with postoperative complications ( p < 0.001). Chemotherapy ( p = 0.775) or radiotherapy ( p = 0.825) were not risk factors for postoperative complications. Conclusions: IR with tissue expander after mastectomy may be a treatment option even when the patients are expected to receive adjuvant chemotherapy or radiotherapy. These results will aid patients who are concerned about the complications of IR caused by chemotherapy or radiotherapy determine whether or not to have IR.
Objectives This study's purpose was to synthesize the literature on design thinking applying nursing education in Korea. Methods A scoping review was conducted by the Joanna Briggs Institute (JBI) methodology (Tricco et al., 2016) suggested by Arksey와 O’Malley (2005). Literature was searched from RISS, KISS, PubMed, and CINAHL. The 303 articles were identified, and 6 were selected for the final analysis. Two reviewers conducted the process independently. Results The six articles were published between 2018 and 2021. In the literature, ‘d. school’ methodology was a major methodology of design thinking. Also, all studies were experimental researches using pre-experimental design in 5 and the other quasi-experimental design. Empathy, critical thinking, and problem-solving competence were significant variables. Conclusions It is considered that the design thinking methodology is a situation that requires the expansion of research. For the experimental studies, well-designed experiments were needed.
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