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The ABC's of metastatic breast cancer

Curing metastatic breast cancer is a great medical challenge requiring improved treatment options. Towards this goal, we need to delineate the mechanisms that trigger metastasis.
The ABC's of metastatic breast cancer
There are nearly a million new breast cancer cases every year, ranking it amongst the leading causes of death among women. Although surgery and therapy are effective, a considerable proportion of patients relapse with metastatic disease and drug resistance.

The EU-funded PTPSMETBC (Roles of SHP2 and other protein tyrosine phosphatases in metastatic breast cancer) project set out to address the events that mediate invasion and colonisation of cancer cells to the metastatic niche in distant organs. Prior work had identified a role for tyrosine phosphatase SHP2 in the motility of triple negative breast cancer cells.

Researchers showed that apart from cell migration, SHP2 also influenced chemotaxis and invasion in vitro. Phosphoproteomics and biochemical analysis unveiled that SHP2 activated several downstream targets and SRC-family kinases through direct interaction. Collectively, these results indicated that SHP2 functioned during the early steps of triple negative breast cancer migration. It also suggested that SHP2 targeting could prevent metastasis formation.

Another part of the project explored the involvement of the C-C chemokine ligand 2 (CCL2) in metastasis. CCL2 secretion by mammary tumours has been reported to recruit CCR2-expressing inflammatory monocytes to primary tumours and metastatic sites.

Researchers observed that CCL2 neutralisation in mice inhibited metastasis by retaining monocytes in the bone marrow. Anti-CCL2 treatment decreased lung metastases, but surprisingly, interruption of CCL2 inhibition led to a metastatic boost and accelerated death. This was attributed to the concerted action of cytokines (IL6, VEGF-A) on cancer cell mobilisation, monocyte release from the bone marrow and angiogenesis. Notably, inhibition of CCL2 and IL-6 markedly reduced metastases and increased survival of the animals.

Taken together, the findings of the PTPSMETBC study provide fundamental insight into the mechanism of breast cancer metastasis. Importantly, the identification of players in the process opens up avenues of intervening with the metastatic mechanism and improving patient outcome.

Related information

Keywords

Breast cancer, metastasis, SHP2, CCL2, IL6
Record Number: 190682 / Last updated on: 2016-12-08
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