J Cancer 2019; 10(12):2800-2810. doi:10.7150/jca.31411

Research Paper

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

Lan Huang1*, Hongfei Ji2,3*, Lei Yin2,3, Xingjian Niu1, Yiran Wang2,3, Yang Liu4, Qijia Xuan1, Liru Li3, Han Zhang1, Xiaoping Zhou1, Jingtong Li1, Chengwei Cui1, Yue Yang2,3, Weiwei An2,3, Qingyuan Zhang1,2,3✉

1. Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin Medical University, Harbin 150081, Heilongjiang, China
2. Institute of Cancer Prevention and Treatment, Harbin Medical University, Harbin 150081, Heilongjiang, China
3. Heilongjiang Academy of Medical Sciences, Harbin 150081, Heilongjiang, China
4. Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin 150081, Heilongjiang, China
*Equal contributions

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Huang L, Ji H, Yin L, Niu X, Wang Y, Liu Y, Xuan Q, Li L, Zhang H, Zhou X, Li J, Cui C, Yang Y, An W, Zhang Q. High Expression of Plakoglobin Promotes Metastasis in Invasive Micropapillary Carcinoma of the Breast via Tumor Cluster Formation. J Cancer 2019; 10(12):2800-2810. doi:10.7150/jca.31411. Available from http://www.jcancer.org/v10p2800.htm

File import instruction

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.

Keywords: Invasive micropapillary carcinoma of the breast (IMPC), Plakoglobin, Metastasis, Anti-anoikis, PI3K pathway