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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Actins / genetics
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Actins / metabolism
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Animals
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Carcinoma, Basal Cell / genetics*
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Carcinoma, Basal Cell / metabolism
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Carcinoma, Basal Cell / secondary
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Cell Line, Tumor
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Cell Movement
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Female
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Gene Expression Regulation, Neoplastic*
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Humans
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Hyaluronan Receptors / genetics*
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Hyaluronan Receptors / metabolism
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Lung Neoplasms / genetics*
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Lung Neoplasms / metabolism
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Lung Neoplasms / secondary
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Lymphatic Metastasis
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Mammary Neoplasms, Experimental / genetics*
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Mammary Neoplasms, Experimental / metabolism
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Mammary Neoplasms, Experimental / pathology
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Mice
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Neoplastic Cells, Circulating / metabolism
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Neoplastic Cells, Circulating / pathology
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Retinoblastoma Protein / antagonists & inhibitors
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Retinoblastoma Protein / genetics*
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Retinoblastoma Protein / metabolism
Substances
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Actins
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CD44 protein, human
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Hyaluronan Receptors
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RNA, Small Interfering
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Retinoblastoma Protein
Grants and funding
This work was supported by Department of Cancer Biology, College of Medicine, University of Cincinnati. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.