Hope in the fight against triple negative breast cancer

Breast cancers are polymorphous but they can be classified in three major categories according to their profile: hormone-dependent cancers, those with an overexpression of the HER2 oncogene and triple negatives, which don’t express any of the three receptors. Specific treatments exist for the first two forms, but up until now, there was nothing for triple negative cancers. Nevertheless, Andrei Turtoi’s team from the University of Liège’s Laboratory of Metastases Research, offers a significant glimmer of hope by unravelling a mechanism involving a protein known as asporin.

Cancer seinThe study (1) published in the journal Plos-Medicine opens the way for specific treatments against triple negative cancers. This type of breast cancer, which concerns 15 % of patients, can only be treated with aggressive chemotherapy, which can nevertheless be applied to different types of cancer. This is not the case for patients with hormone-dependent cancer expressing hormone receptors (oestrogen and progesterone), who will be prescribed hormonal treatments after classic chemotherapy, radiotherapy and/or surgery; this is also the case for those whose tumour has an excess of HER2 receptors – which promotes the growth of cancer cells. They will receive a targeted treatment in order to block these receptors and slow down the tumor growth.

A clean war

“Targeted treatments are, by definition, treatments that will specifically attack the tumour according to its particular characteristics”, explains Professor Vincent Castronovo, who supervised the study conducted by the University of Liège’s GIGA Laboratory of Metastases Research, with Dr. Andrei Turtoi. “This targeted action can therefore act on the tumour’s functional characteristics, i.e. deliver a specially targeted toxic load to the tumour, without damaging the non-cancerous cells. In the first case, the treatment targets cell’s specific biochemical characteristics. Unfortunately, such treatments often provoke tumor resistance because of the heterogeneity of the cancers cells. This situation leaves us with no more weapons to fight the cancer. Therefore, we have opted for toxic targeted treatments that will allow us to deliver a toxic load (biological, chemical, radioactive) to the place where the cancer cells are located, thus killing all the cancer cells locally, whatever their characteristics. A sort of clean war, with a minimum of collateral damage. But for this to work, it’s essential to identify the specific tumor targets. That’s why it is important to discover biomarkers that are reachable (or better said accessible) by targeted therapies. Importantly, they should be present in the cancerous tissues and those surrounding them, but absent in the healthy tissue.”

The researchers from Liège, who have already developed and patented an innovative technique to find these accessible biomarkers, are also proposing approaches to use these new targets as treatments. “During our research, we became interested in the protein called asporin. One of its variants had already been revealed by a Japanese team, and was known to be involved in joint diseases such as arthritis. However, its role or involvement in cancer was as yet unknown.

A protective wall…

Asporin was rapidly identified as an essential element that could intervene in the fight against triple negative breast cancer. “This molecule is produced by the fibroblasts in the breast’s stroma, when cancer cells attempt to develop. It binds and blocks the activity of TGF-β1 that is the paramount growth factor promoting cancer cell invasion, immunosuppression and metastasis. Asporin therefore plays the role of a protective wall to prevent the cancer cells from growing and invading the healthy tissue and forming metastases. The stroma tries to protect us but some of the cancer cells manage to force it to collaborate to fuel their growth. This is the case for the most aggressive malignant cells, but not just for any of them: we observed that, contrary to what happens in the presence of hormone receptor positive cancer cells, ‘triple negative’ and HER2+ cancer cells (to a lesser extent) can give the order to normal breast cells to stop producing asporin, giving them free rein to grow. They will then be able to invade the breast and form metastases, which remain the main cause of cancer mortality and morbidity. This is what explains the aggressiveness of this type of breast cancer."

(1) Pamela Maris, Arnaud Blomme, Ana Perez Palacios, Brunella Costanza, Akeila Bellahcène, Elettra Bianchi, Stephanie Gofflot, Pierre Drion, Giovanna Elvi Trombino, Emmanuel Di Valentin, Pino G. Cusumano, Sylvie Maweja, Guy Jerusalem, Philippe Delvenne, Eric Lifrange, Vincent Castronovo, Andrei Turtoi , Asporin Is a Fibroblast-Derived TGF-β1 Inhibitor and a Tumor Suppressor Associated with Good Prognosis in Breast Cancer , September 01, 2015, PLOS Medicine, DOI: 10.1371/journal.pmed.1001871

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