Drug Discovery Opinion

Nearly half of all patients treated for apparently localised breast cancer develop metastatic disease. Although there are treatment options that prolong survival and improve quality of life for patients with metastatic breast cancer, these treatments rarely lead to long-term survival without disease recurrence. The most common sites of metastases are the bones, the liver and the lungs: breast cancer is the most common origin of metastatic deposits in the skeleton.

Researchers from Tufts University have now identified Rho-associated kinase (ROCK) as a potential target to reduce breast cancer metastasis. Signalling through ROCK plays a key role in regulating cell adhesion and motility and aberrant expression of ROCK has been linked to metastasis. In the present study, the team showed that ROCK expression is increased in metastatic human mammary tumours and breast cancer cell lines compared with non-metastatic tumours and cell lines. A metastatic phenotype could also be induced in a cell line that is not normally metastatic by over-expression of ROCK.

In a novel mouse model of “human breast cancer metastasis to human bone”, inhibiting ROCK in the earliest stages of breast cancer decreased metastatic tumour mass in bone by 77% and overall frequency of metastasis by 36%. ROCK function could be effectively blocked by either ROCK-targeting short hairpin RNA (shRNA) or by the specific ROCK inhibitor, Y27632. Expression of the microRNA cluster, c-Myc-regulated miR-17-92 was found to be elevated in metastatic breast cancer cells compared with non-metastatic cells and reduced by treatment with Y27632. Blockade of miR-17 was further shown to decrease breast cancer cell invasion/migration in vitro and metastasis in vivo. The authors suggest that the effects of ROCK may be mediated by modulating the c-Myc pathway, including c-Myc-dependent microRNAs. They propose that inhibition of ROCK, or the pathway it stimulates, may represent a novel approach for treatment of breast cancer metastases.

The study is published in the journal Cancer Research.

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