By: Hsuan-Hua Huang

In recent decades, breast cancer has been one of the leading causes of death in women. Finding the mutate gene that directly or indirectly affects the rate of getting cancer is fairly important. Human epidermal growth factor receptor 2, abbreviated as HER2, has been identified to be expressed in approximately 15%-30% of breast cancer (Schmitt, 2013). Thus, the mutation of HER2 will actually increase a person’s chance to grow a tumor within their breast. There are also some other elements that will affect the growth of mutation in HER2, such as microRNA or chromosome 17 polysomy. MicroRNA and chromosome 17 polysomy can help us understand how tumors are form and how to use those relative elements to suppress the growth and enhance the cancer treatment to work more effectively.

HER2 gene is locate on chromosome 17. Chromosome 17 is the regulator for cellular signaling and that helps to regulates the cell development and cell growth within our body. Chromosome 17 polysomy, which is when the cell has 3 or more copies, is somewhat related to the growth of tumors. HER2 is one of the EFGR family, it encodes a protein of 185 kDa that deals with tyrosine kinase activities. Protein expression and HER2 amplification are great methods to help predict tumor response or resistance to different type of cancer treatments. Trastuzumab is one of the current cancer therapies, it can help to suppress cancer cell by inhibiting proliferation of tumor cells over expressing the HER2 protein. Trastuzumab can be used as a single agent or in combination with other type of chemotherapy to treat breast cancer patients. Therefore, detection of the HER2/neu alternations or protein expression in tumors is very important for trastuzumab treatment (Zhu et al. 2013).

In a present study, 27.8% of tumors showed chromosome 17 polysomy, and HER2 amplification tumors were likely to have chromosome 17 than those cases that had no HER2 amplification (Zhu et al. 2013). Zhu et al. used fluorescence in situ hybridization and immunohistochemistry for HER2 protein expression in a cohort of 481 patients. Zhu et al. (2013) found out that polysomy 17 did not influence HER2 protein expression in IHC 2+ nonamplified tumors. The frequency of polysomy was correlated with the HER2 copy number and partially contributed to HER2/neu amplification but not HER2 protein expression (Zhu et al. 2013). As a result, polysomy 17 may have contributed to the copy number in tumors with HER2 amplification, but it does not significantly influence HER2 protein expression. However, researchers must develop more experiments to verify this study.

Breast cancer is a heterogeneous disease, which mean its tumors are heterogeneous in morphological perspective. This ideology also applied to the therapy for breast cancer. Targeting HER2 mutation can help predict a person’s likelihood to get breast cancer. One way to estimate the likelihood of a person increase the probability to get breast cancer is to investigated whether a person’s HER2 gene is amplification negative. It show that those people who have HER2 mutation positive will likely to be benefit from HER2 targeted drugs (Bose et al. 2013). In order to find the best treatment for the tumors in patient, microRNA can be use to find out the location in the HER2 gene.

MicroRNA helps to regulate major cellular process involved in tumor biology, which including cell proliferation, apoptosis, and metastasis (Fang et al. 2013). MicroRNA are a class of small noncoding, single stranded RNAs. MicroRNA is bonded partially to 3′ untranslated regions of target gene partially. MicroRNA can act as oncogenes or oncosuppressors, which mean microRNA is very important in determined whether it can cause tumor to grow or to suppressed its growth. MiR-1990-5p is one of the cancer related gene in microRNA. MiR-1990-5p have been found being related to multiple type of cancers, such as medulloblastoma, colorectal cancers, and renal cell carcinoma. Therefore, exploring MiR-1990-5p might help the researchers to understand whether it will be highly associated with breast cancer. Fang et al. (2013) discovered that miR-1990-5p inhibited HER2 gene expression by direct targeting its 3’UTR and inhibited the activation of the HER2 downstream signal pathway mediator ERK1/2 and AKT. ERK1/2 and AKT work as the activation of HER2 downstream signal pathway mediators. The expression of miR-1990-5p will inhibit BT-474 and SK-BR-3’s clonogenicity and expression (Fang et al. 2013). MiR-199b-5p will target HER2 ‘s 3′ UTR (3’ untranslated region) and cause it to inhibit HER2 expression in breast cancer cells. From here, it seems that targeting miR-199b-5p in HER2 with cancer drug can help to treat tumor more efficiently compare to using the cancer drug to treat the whole HER2 gene.

Overexpression of miR-199b-5p decreased HER2 protein expression in SK-BR-3 and BT-474 (Fang et al. 2013). MiR-199b-5p showed no effect on HER2 mRNA level in the qRT- PCR2 analysis of HER2 (Fang et al. 2013) suggests that miR-199b-5p negatively regulates HER2 expression at the translational level. The cancer cell can migrate throughout the organs, so it is important to find way to stop the migration in the tumor cells. Over expression of miR-199b-5p significantly inhibited the ability of SK-BR-3 and BT-474 cells to migrate through insert membrane (Fang et al. 2013). MiR-199b-5p can help to inhibits the migration and the survival of breast cancer cells and have the potential to act as alternative therapeutic target for HER2-positive breast cancer. These results strongly suggest that over expression of miR-199b-5p in HER2-positive breast cancer cells can interfere with the aggressive phenotype by direct suppressing HER2 expression (Fang et al. 2013).

Fang et al. used cell colony-forming assay to showed the enhanced effect of miR-199b-5p on trastuzumab-inhibited cell clonogenicity. Trastuzumab is one of the widely used drugs to treat patients with breast cancer, it is a humanize specific monoclonal antibody that work against the HER2 protein. However, to find whether a person’s cancer cell will resist the drug is fairly important. Without knowing whether a type of gene will suppress the function of cancer drug, it might eliminate the function of the cancer drug and cause recurrence of spreading of cancer cells. MiR-199b-5p can work as a new oncosuppressor gene in breast cancer by interfering with the aggressive phenotype mediated by HER2 and enhance the effect of trastuzumab treatment.

HER2 gene amplification is a major therapeutic target in breast cancer and it is the clinical criterion for the use of U.S. Food and Drug Administration-approved, HER2-targeted drug, which currently are trastuzumab, pertuzumab, lapatinib (Bose et al. 2013). To determine which drug can work well to focus a specific type of mutation within HER2 gene is very important. This can help us to treat the breast tumor cells more efficiently. HER2 somatic mutations can be used to determine whether a cancer drug can work efficiently to suppress those mutation in HER2. Bose et al. (2013) identified 13 HER2 somatic mutations in their study, and find out one mutation, del.755-759, had increased phosphorylation of HER2’s heterodimerization parts, such as EGFR and HER3. HER2 del.755-759 is homologous to EGFR exon 19 deletions, which produce gefitnib-sensitive NSCLC (Bose et al. 2013). From here, we can see this HER2 mutation, del.755-759, will also have influence in the cancer expression.

Mutations in HER2 in a patient can sometimes help the doctor to see which type of cancer drug can work better on this patient. Recurrence is a good predictor for the function of HER2 and cell behavior. Bose et al. (2013) found that Neratinib was a very potent inhibitor for all of the HER2 mutations and Trastuzumab did reduce the formation of invasive appearing colonies in the Matrigel assay on MCF10A cells but did not seem to be a cytotoxic effect from this drug. From here, cancer drug like Trastuzumab has a complex mechanism of action, it can help to suppress the mutations within HER2, but it can’t used to suppress all type of mutations. Thus, further study for Trastuzumab cancer therapy in cancer cells is required.

In conclusion, breast cancer does not compose a single type of mutations. It is actually contain multiple types of mutations. One type of cancer drug can’t be used to cure all kind of mutations in HER2, different types of cancer drug have different function in suppressing the different mutations. Using genetic methods to find those specific gene mutations in HER2 can help doctors understand which kind of breast cancer a patient has. In order to treat a patient more efficiently, it is always helpful to estimate which type of HER2 somatic mutation a patient has when she is in the early stage of breast cancer. These genetic finding help us understanding the importance of genetics in treating the disease and can help the medical field to cure, or prevent breast cancer with better efficiency.

Works Cited

Bose, Ron, et al. “Activating HER2 Mutations in HER2 Gene Amplification Negative Breast Cancer.” Cancer Discovery, vol. 3, no. 2, Dec. 2012, pp. 224–37, https://doi.org/10.1158/2159-8290.cd-12-0349.

Fang, Chen, et al. “MiR-199b-5p Targets HER2 in Breast Cancer Cells.” Journal of Cellular Biochemistry, vol. 114, no. 7, May 2013, pp. 1457–63, https://doi.org/10.1002/jcb.24487. Accessed 23 Jan. 2020.

Schmitt, Fernando. “HER2+ Breast Cancer: How to Evaluate?” Advances in Therapy, vol. 26, no. S1, July 2009, pp. 1–8, https://doi.org/10.1007/s12325-009-0046-1. Accessed 5 Mar. 2020.

Zhu, Xiaoli, et al. “Genetic Alterations and Protein Expression of HER2 and Chromosome 17 Polysomy in Breast Cancer.” Human Pathology, vol. 42, no. 10, Oct. 2011, pp. 1499–504, https://doi.org/10.1016/j.humpath.2010.04.023. Accessed 19 Jan. 2023.