Abstract
Basal-like breast carcinomas (BLCs) present with extratumoral lymphovascular invasion, are highly metastatic, presumably through a hematogenous route, have augmented expression of CD44 oncoprotein and relatively low levels of retinoblastoma (Rb) tumor suppressor. However, the causal relation among these features is not clear. Here, we show that Rb acts as a key suppressor of multiple stages of metastatic progression. Firstly, Rb suppresses collective cell migration (CCM) and CD44-dependent formation of F-actin positive protrusions in vitro and cell-cluster based lymphovascular invasion in vivo. Secondly, Rb inhibits the release of single cancer cells and cell clusters into the hematogenous circulation and subsequent metastatic growth in lungs. Finally, CD44 expression is required for collective motility and all subsequent stages of metastatic progression initiated by loss of Rb function. Altogether, our results suggest that Rb/CD44 pathway is a crucial regulator of CCM and metastatic progression of BLCs and a promising target for anti-BLCs therapy.
Highlights
Migration of cancer cells is an initial step in multistep process of metastasis during which malignant cells spread from the primary tumor to distant organs [1]
To test our hypothesis that loss of Rb function can initiate collective cell migration (CCM), we examined the effect of Rb knockdown (Figure 1A) on collective and single cell-based migration in vitro
These results indicate that suppression of Rb expression preferentially stimulates CCM over single cell migration (SCM) in vitro
Summary
Migration of cancer cells is an initial step in multistep process of metastasis during which malignant cells spread from the primary tumor to distant organs [1]. Invasive breast carcinoma cells may hijack this or similar mechanisms and reactivate CCM in response to suitable oncogenic stimuli. BLCs have poor prognosis, exhibit resistance to anti-estrogen therapy, and lack any known clinicallyproven therapeutic target such as Her-2. Their major histopathological features, in addition to lymphovascular invasion, are extensive necrosis in the primary tumor and metastatic spread to the lungs and brain [4]. The molecular mechanism of lymphovascular invasion, its potential role in dissemination of circulating cancer cells (CCC) and the subsequent colonization of the target organ are poorly understood
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