Loss of Kaiso expression in breast cancer cells prevents intra-vascular invasion in the lung and secondary metastasis

The metastatic activity of breast carcinomas results from complex genetic changes in epithelial tumor cells and accounts for 90% of deaths in affected patients. Although the invasion of the local lymphatic vessels and veins by malignant breast tumor cells and their subsequent metastasis to the lung, has been recognized, the mechanisms behind the metastatic activity of breast tumor cells to other distal organs and the pathogenesis of metastatic cancer are not well understood. In this study, we utilized derivatives of the well-established and highly metastatic triple negative breast cancer (TNBC) cell line MDA-MB-231 (MDA-231) to study breast tumor metastasis in a mouse model. These MDA-231 derivatives had depleted expression of Kaiso, a POZ-ZF transcription factor that is highly expressed in malignant, triple negative breast cancers. We previously reported that Kaiso depletion attenuates the metastasis of xenografted MDA-231 cells. Herein, we describe the pathological features of the metastatic activity of parental (Kaiso^positive) versus Kaiso^depleted MDA-231 cells. Both Kaiso^positive and Kaiso^depleted MDA-231 cells metastasized from the original tumor in the mammary fat pad to the lung. However, while Kaiso^positive cells formed large masses in the lung parenchyma, invaded large pulmonary blood vessels and formed secondary metastases and large tumors in the distal organs, Kaiso^depleted cells metastasized only to the lung where they formed small metastatic lesions. Importantly, intravascular invasion and secondary metastases in distal organs were not observed in mice xenografted with Kaiso^depleted cells. It thus appears that the lung may constitute a barrier for less invasive breast tumors such as the Kaiso^depleted TNBC cells; this barrier may limit tumor growth and prevents Kaiso^depleted TNBC cells from invading the pulmonary blood vessels and forming secondary metastases in distal organs.