Abstract
Bone marrow stromal antigen 2 (BST-2) mediates various facets of cancer progression and metastasis. Here, we show that BST-2 is linked to poor survival in invasive breast cancer patients as its expression positively correlates with disease severity. However, the mechanisms that drive the pro‐metastatic functions of BST-2 are not fully understood. Correlation of BST-2 expression and tumor aggressiveness was analyzed in human tissue samples. Migration, invasion, and competitive experimental metastasis assays were used to measure the cellular responses after silencing BST-2 expression. Using a mouse model of breast cancer, we show that BST-2 promotes metastasis independent of the primary tumor. Additional experiments show that suppression of BST-2 renders non-adherent cancer cells non-viable by sensitizing cells to anoikis. Embedment of cancer cells in basement membrane matrix reveals that silencing BTS-2 expression inhibits invadopodia formation, extracellular matrix degradation, and subsequent cell invasion. Competitive experimental pulmonary metastasis shows that silencing BST-2 reduces the numbers of viable circulating tumor cells (CTCs) and decreases the efficiency of lung colonization. Our data define a previously unknown function for BST-2 in the i) formation of invadopodia, ii) degradation of extracellular matrix, and iii) protection of CTCs from hemodynamic stress. We believe that physical (tractional forces) and biochemical (ECM type/composition) cues may control BST-2’s role in cell survival and invadopodia formation. Collectively, our findings highlight BST-2 as a key factor that allows cancer cells to invade, survive in circulation, and at the metastatic site.
Highlights
Metastasis is the primary cause of all cancer deaths, including breast cancer, the mediators of metastasis have not been fully discovered
We utilized publicly available data sets to analyze the levels of BST-2 transcript (TCGA)[3,4] and protein (Human Protein Atlas)[7] to show that high levels of BST-2 positively correlates with features of aggressive breast cancer, such as survival, invasion, migration, and metastasis[3,4,7]
In terms of disease severity, BST-2 level is highest in tumors of invasive breast cancer (IBC) patients with synchronous IBC followed by those that presented with a 2nd metachronous IBC (Fig. 1B)
Summary
Metastasis is the primary cause of all cancer deaths, including breast cancer, the mediators of metastasis have not been fully discovered. In the absence of complete cure for breast cancer, it is important to identify unknown drivers of cancer progression and metastasis to address outstanding questions related to how tumor cells acquire metastatic competency to colonize a different organ with a distinct microenvironment. BST-2 was shown to possess viral tethering activity because it was discovered to be the host protein that HIV-1 viral protein U (Vpu) must counteract for viral particles to be released from infected cells[13,14]. Increased expression of BST-2 in breast cancer has been shown to mediate various facets of breast cancer progression including cell adhesion, anchorage-independent growth, survival, primary tumor growth, invasion, and metastasis. We found that the cellular mechanism by which BST-2 exerts its pro-metastasis function includes the ability of BST-2 to promote i) formation of invasive structures, ii) survival of cancer cells in circulation, and iii) enhancement of pulmonary seeding of cancer cells and malignant growth of such cells in the metastatic site
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
