Research Briefs, Science & Technology

Discovery of new mechanisms elucidates breast cancer metastasis

Finding more effective drugs that target certain aggressive forms of breast cancer first requires a deeper understanding of the disease’s progression mechanisms. The need for increased insight into the mitigation of breast cancer growth fueled a seven-year-long study at the Research Institute of the McGill University Health Centre (RI-MUHC).

Nathalie Lamarche-Vane, a professor in McGill’s Department of Anatomy and Cell Biology, and her team investigated the molecular and cellular processes underpinning the metastasis of breast cancer. 

“This study goes deeply into the mechanism of metastasis to show the role of this molecule [CdGAP] as an important driver of metastasis,” Lamarche-Vane said in an interview with The Tribune

Metastasis is a key step in the growth of a cancer, during which cancer cells detach from the primary tumour and migrate to take over distant organs. Understanding the mechanisms driving this phenomenon is crucial because it constitutes the primary cause of mortality among breast cancer patients.

Since the subtype of breast cancer known as HER2+ amounts to nearly one-third of breast cancer cases with early-stage metastasis, the study focused on this specific type. While previous research has linked high expression of CdGAP with poor survival rates in HER2+ cancer, Lamarche-Vane’s research sheds light on the role of CdGAP in the tumorigenesis and metastasis caused by HER2+.

“This protein, [CdGAP], was discovered 20 years ago, [and] it’s really step by step that we came to the idea that it may have some role in cell migration and cell proliferation,” Lamarche-Vane said. “To our surprise, [the mouse breast cancer cell lines used as a research model] were having a high level of expression of CdGAP and that is what caught our attention, because normally, this protein, because of its known roles as a regulator of small GTPase enzymes, it should have been [suppressing rates of tumour growth rather than increasing them].”

The researchers established that CdGAP promotes HER2+ breast cancer growth and is instrumental in its metastatic evolution. CdGAP interacts with the adaptor protein talin to act as a transcriptional target for the TGF-β signaling, a crucial factor in cancer development. More specifically, CdGAP modulates an epithelial-mesenchymal transition (EMT), which enables tumour dissociation by functioning as a molecular target of the TGF-β pathway. 

They also identified talin as a protein interacting with CdGAP to regulate focal adhesions, mechanical structures allowing cell movement, and integrin activation, which signals to the cell that it is time to get ready to move. These molecular processes collectively contribute to the enhanced migration, invasion, and adhesion of cancer cells, ultimately fueling the aggressive metastatic progression of HER2+ breast cancer.

Lamarche-Vane and her team’s dedication to investigating CdGAP and unraveling the foundational science described above has paved the way for the eventual breakthrough of a new therapy against HER2+ breast cancer. 

“The difficulty [in devising a drug against CdGAP] is that this is not like a receptor,” Lamarche-Vane said. “So when you have a receptor at the surface, […] you can design the molecules to block the binding to the ligands or antibodies. The CdGAP is [instead] a molecule that is inside the cell, in the cytoplasm. So to derive drugs becomes a bit more difficult, but it is feasible. There is some indication that that could be the future.”

Although Lamarche-Vane acknowledged that this paper has been funded by the Canadian Institutes of Health Research (CIHR), she emphasized the bleak reality that fundamental research like this, which aims to establish a foundation on which future life-saving discoveries can be built, is widely under-funded

“This is [fundamental] science, but then it’s the future, it takes time, it takes years, but this is what will lead, eventually, to [more practical discoveries such as] therapeutics,” Lamarche-Vane said.

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