Abstract
Rho-associated kinase (ROCK) signaling plays a fundamental role in regulating cell morphology, adhesion, and motility. Aberrant expression of ROCK is related to tumor metastases and poor clinical outcome. Here, we show that ROCK expression is increased in metastatic human mammary tumors and breast cancer cell lines compared with nonmetastatic tumors and cell lines. Overexpression of ROCK confers a metastatic phenotype on the nonmetastatic MCF-7 cell line. Inhibition of ROCK activity, by either a specific ROCK inhibitor (Y27632) or ROCK-targeted small interfering RNAs, reduces cell migration and proliferation in vitro and metastasis to bone in vivo using a novel "human breast cancer metastasis to human bone" mouse model. Expression of the c-Myc-regulated miR-17-92 cluster is shown to be elevated in metastatic breast cancer cells compared with nonmetastatic cells and diminished by Y27632 treatment. Furthermore, blockade of miR-17 is shown to decrease breast cancer cell invasion/migration in vitro and metastasis in vivo. Together, these findings suggest that augmented ROCK signaling contributes to breast cancer metastasis. The effects of ROCK on tumor cell invasion/motility and growth may derive from regulating cytoskeletal actin-myosin contraction and modulating the c-Myc pathway, including c-Myc-dependent microRNAs. Inhibition of ROCK or the pathway it stimulates, therefore, may represent a novel approach for treatment of breast cancer metastases.
Highlights
Breast cancer is by far the most common cancer among women and the fifth most common cause of cancer death worldwide
We investigate Rho-associated kinases (ROCK)-induced molecular events that may be responsible for breast cancer metastases using in vitro assays and the murine “human breast cancer metastasis to human bone” model in which breast cancer cells metastasize from the orthotopic site [11]
To investigate the potential role of ROCK signaling in regulation of breast cancer metastasis, we assessed the expression of ROCK in human breast cancer specimens and cell lines
Summary
Breast cancer is by far the most common cancer among women and the fifth most common cause of cancer death worldwide. The primary tumor often causes significant morbidity, metastasis to distant organs accounts for >90% of breast cancer– related mortality. The underlying mechanisms responsible for breast cancer metastasis have not yet been elucidated. There is little in the way of metastasis-specific therapy. Members of Rho small GTPases play a role in regulating cell morphology, growth, apoptosis, and motility. The Rho-associated kinases (ROCK), of which there are two isoforms, ROCK1 and ROCK2 (here called ROCK), are principal mediators of Rho small GTPases. ROCK is implicated in the regulation of breast cancer metastasis. A clinical study showed that increased expression of ROCK corresponds to late-stage tumors and metastases and is negatively
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