Fighting HER2+ Breast Cancer with the Immune System

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In the late 70s, scientists discovered that the body contains certain cancer-causing genes, which if mutated, lead to the development of cancer. This discovery unleashed a flurry of research in which scientists tried to identify genes that could be directly implicated in cancer. Scientists found one such gene – the HER2 gene – which is overexpressed in about 20% of breast cancers. This cancer was thus named HER2+ breast cancer. It is a particularly aggressive form of breast cancer; it typically does not respond to traditional chemotherapy, and patients with HER2+ breast cancer have a higher likelihood of cancer recurrence.

The HER2 gene codes for the HER2 is a receptor which, along with other receptors, plays an important role in regulating a variety of (sometimes contradictory) processes including cell growth, cell proliferation, and apoptosis (cell death when something in the cellular machinery goes very wrong). In normal cells, the activity of HER2 and the associated cell-signaling pathways is very strictly regulated.

The mutation causing this cancer leads to an overexpression of HER2 receptors, which in turn leads to the activation of signaling pathways that enhance cell survival and the suppression of the action of proteins that prevent the growth of damaged cells, both of which lead to the formation of tumors.

While most chemotherapy treatments have been ineffective at treating HER2+ type breast cancer, targeted immunotherapy in the form of trastuzumab has been effective in improving outcomes. Trastuzumab is a monoclonal antibody that binds to the HER2 receptor, which prevents HER2 from binding to the other receptors that are necessary for the activation of the signaling pathways that lead to tumor growth. The antibodies also activate the body’s immune system, which recruits cells that release cytotoxic chemicals into the environment surrounding the tumor cells, ultimately killing them.

While trastuzumab has improved the prognosis of HER2+ breast cancer patients – in some studies, the median overall survival has increased by nearly 5 years – many patients develop resistance against trastuzumab. This is often because the shape and structure of the HER2 receptor in tumor cells undergoes a change, due to which trastuzumab can no longer bind to HER2 and can no longer prevent it from activating signaling pathways. Further research into different targeted drugs is currently underway and in 2019, the Food and Drug Administration (FDA) approved another antibody, atezolizumab, to treat breast cancer.

References:
More on the discovery of the HER2 gene: https://www.gene.com/stories/her2/
How trastuzumab works: https://www-nejm-org.proxy.library.emory.edu/doi/full/10.1056/NEJMra043186
More on immunotherapies to threat HER2+ breast cancer: https://www.nature.com/articles/s41523-020-0153-3