“A Review of HER2 overexpression and somatic mutations in cancers”

Human Epidermal Growth Factor Receptor 2 (HER2) is a gene that encodes a growth factor receptor, which activates intracellular signalling pathways in response to extracellular messengers called growth factors. These intracellular mechanisms lead to regulated cell growth and embryonic development, which, when unregulated, whether through the mutation or overexpression of HER2, can lead to the development of cancers (Gutierrez and Schiff, 2011, Iqbal and Igbal, 2014, Moasser, 2007).

HER2 overexpression and mutation has been discovered in many cancers, including breast, colorectal, bladder, gastric, oesophageal, endometrial, and ovarian cancers. The presence of overexpression or somatic mutations which cause dysregulation of HER2 in these cancers can determine treatment and treatment-associated outcomes. In breast and ovarian cancers, HER2 overexpression offers prognostic value regardless of the type of treatment administered (or if there is no treatment), as it signals a more aggressive and lethal form of cancer (Iqbal and Iqbal, 2014, Chan et al., 2012, Huang et al., 1999). The cancers that test positive for increased HER2 activity are called HER2-positive cancers and have been given differential treatment, such as HER2-targeted drugs like Trastuzumab, which are administered most prominently in breast and gastroesophageal cancers (Iqbal and Iqbal, 2014).

HER2-targeting therapies have been shown to often be effective as HER2 is an oncogene-addicting gene, meaning that tumours depend on increased HER2 activity/expression for its survival, as when the gene has been suppressed in vitro and in vivo, this has formerly been shown to lead to tumour regression (Gutierrez and Schiff, 2011). HER2 targeting therapies have shown some effectiveness in increasing survival and reducing cancer progression, which can be seen in breast cancer, which, although normally has a worse prognosis with HER2 overexpression, reverses to have a better prognosis under HER2-targeted therapy (Chan et al., 2012, Lei et al., 2017).

In this review, we present how the mechanism of the disruption of the HER2 gene can shift cells from undergoing their normal pathway of controlled growth to an oncogenic pathway. Our objectives are specifically to present all the main information we know about the normal, non-oncogenic pathway of HER2 and how it is regulated. We then aim to note all the currently known mechanisms that are altered in HER2-positive cancers, and how they contribute to cancer’s survival and growth. We also aim to differentiate HER2 overexpression from HER2 somatic mutations leading to overactivation and present their similarities and differences in relation to oncogenesis in this review. To do this, over-activating HER2-mutants will be defined as somatic mutants in HER2 which either prolong or increase the intensity of HER2’s downstream signalling through a means which is not overexpression, though many of these mutants may also cause the overexpression of HER2. We believe this will lead to a greater understanding of all the currently known mechanisms of HER2-based oncogenesis in the literature and will summarise why the HER2 gene is so significant in the proliferation of different cancers.

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