Dataset Information

High Expression of Plakoglobin Promotes Metastasis in Invasive Micropapillary Carcinoma of the Breast via Tumor Cluster Formation.

ABSTRACT: Invasive micropapillary carcinoma of the breast (IMPC) is a rare subtype of breast cancer that has a high frequency of lymph node (LN) involvement and metastasis to distant organs. IMPC is characterized by distinct histomorphology and unfavorable prognosis when compared with invasive ductal carcinoma no special type (IDC-NST). However, the underlying molecular mechanisms remain unclear. We reported here that plakoglobin, as a key component in cell adhesion, can promote collective metastasis through facilitating IMPC clusters formation. In comparing the clinicopathological features of 451 IMPC patients and 282 IDC-NST patients, our results showed that tumor emboli were significantly higher in IMPC patients and were associated with a high frequency of metastasis. Both in vitro and in vivo data showed overexpression of plakoglobin in both the cell membrane and the cytoplasm of IMPC clusters. When plakoglobin was knocked down in IMPC cell models, the tumor cell clusters were depolymerized. Using mouse models, we validated the metastatic potential of tumor clusters was higher than single cells in vivo. Further analysis showed that higher expression of plakoglobin was able to promote activation of the PI3K/Akt/Bcl-2 pathway, which might protect the clusters from anoikis. Our data indicate that plakoglobin promotes tumor cluster formation in IMPC and downregulates apoptosis in the cell clusters through activation of PI3K/Akt/Bcl-2 signaling. These results provide a convincing rationale for the high metastatic propensity seen in IMPC.

SUBMITTER: Huang L

PROVIDER: S-EPMC6584935 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

High Expression of Plakoglobin Promotes Metastasis in Invasive Micropapillary Carcinoma of the Breast via Tumor Cluster Formation.

Huang Lan L Ji Hongfei H Yin Lei L Niu Xingjian X Wang Yiran Y Liu Yang Y Xuan Qijia Q Li Liru L Zhang Han H Zhou Xiaoping X Li Jingtong J Cui Chengwei C Yang Yue Y An Weiwei W Zhang Qingyuan Q

Journal of Cancer 20190602 12

Invasive micropapillary carcinoma of the breast (IMPC) is a rare subtype of breast cancer that has a high frequency of lymph node (LN) involvement and metastasis to distant organs. IMPC is characterized by distinct histomorphology and unfavorable prognosis when compared with invasive ductal carcinoma no special type (IDC-NST). However, the underlying molecular mechanisms remain unclear. We reported here that plakoglobin, as a key component in cell adhesion, can promote collective metastasis thro ...[more]

PMID: 31258788

Similar Datasets

Project description:Abstract Background and purpose: Machine learning (ML) is applied for outcome prediction and treatment support. This study aims to develop different ML models to predict risk of axillary lymph node metastasis (LNM) in breast invasive micropapillary carcinoma (IMPC) and to explore the risk factors of LNM. Methods From the Surveillance, Epidemiology, and End Results (SEER) database and the records of our hospital, a total of 1547 patients diagnosed with breast IMPC were incorporated in this study. The ML model is built and the external validation is carried out. SHapley Additive exPlanations (SHAP) framework was applied to explain the optimal model; multivariable analysis was performed with logistic regression (LR); and nomograms were constructed according to the results of LR analysis. Results Age and tumor size were correlated with LNM in both cohorts. The luminal subtype is the most common in patients, with the tumor size <=20mm. Compared to other models, Xgboost was the best ML model with the biggest AUC of 0.813 (95% CI: 0.7994 - 0.8262) and the smallest Brier score of 0.186 (95% CI: 0.799-0.826). SHAP plots demonstrated that tumor size was the most vital risk factor for LNM. In both training and test sets, Xgboost had better AUC (0.761 vs 0.745; 0.813 vs 0.775; respectively), and it also achieved a smaller Brier score (0.202 vs 0.204; 0.186 vs 0.191; 0.220 vs 0.221; respectively) than the nomogram model based on LR in those three different sets. After adjusting for five most influential variables (tumor size, age, ER, HER-2, and PR), prediction score based on the Xgboost model was still correlated with LNM (adjusted OR:2.73, 95% CI: 1.30-5.71, P=0.008). Conclusions The Xgboost model outperforms the traditional LR-based nomogram model in predicting the LNM of IMPC patients. Combined with SHAP, it can more intuitively reflect the influence of different variables on the LNM. The tumor size was the most important risk factor of LNM for breast IMPC patients. The prediction score obtained by the Xgboost model could be a good indicator for LNM.

Project description:The molecular mechanisms that underpin invasive ductal breast cancer (IDC) invasion and metastasis are incompletely understood. The oncogene, mouse double minute 2 (MDM2), has been implicated in the pathogenesis of numerous cancers, where it stimulates the expression of matrix metalloproteinase 9 (MMP9), an important enzyme in the breakdown of the extracellular matrix. However, its role in breast cancer remains poorly understood. This study assessed the clinical significance of MDM2 expression in IDC and used in vitro expression assays to determine the molecular roles of MDM2. Immunohistochemical staining for MMP9 and MDM2 was performed using archived tumor blocks from 321 women who underwent surgical resection for IDC at the First Affiliated Hospital of Nanjing Medical University, China between January 2002 and December 2003. MCF-7 and MDA-MD-231 cell lines were transfected with siRNA targeted against MDM2, or MDM2 was overexpressed using transiently expressed vectors. The invasion, cell migration and proteolytic capabilities of cells that over- or underexpressed MDM2 was then assessed and compared against control cells, in addition to the consequent effects on MMP9 expression using RT-PCR. In vivo, 54.9% and 49.6% of samples were positive for MMP9 and MDM2 expression, respectively, and their expression was significantly correlated (r² = 0.171, P = 0.012). Moreover, MDM2 expression was markedly correlated with disease-free survival (HR 2.56, 95% CI 1.02-6.40, P = 0.038). In vitro, MDM2 overexpression significantly enhanced cell invasion, migration and proteolysis compared with control cells, and the converse effects were observed after MDM2-siRNA treatment. MDM2 overexpression induced MMP9 expression in a dose-dependent manner. Taken together, these results suggest that high levels of MDM2 are associated with a poorer prognosis in IDC. This might result from increased tumor invasiveness due to enhanced MMP9 expression causing increased extracellular matrix breakdown.

Dataset Information

High Expression of Plakoglobin Promotes Metastasis in Invasive Micropapillary Carcinoma of the Breast via Tumor Cluster Formation.

Publications

High Expression of Plakoglobin Promotes Metastasis in Invasive Micropapillary Carcinoma of the Breast via Tumor Cluster Formation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets