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.