NVOLVE

View Original

Key Biomarkers in Breast Cancer and the Positive HER2 Gene

Ana Baide

By Khadijah Walker, Homa Keshmiri

Abstract:  

This research paper explores the functions, uses, and detections of key biomarkers, in addition to emphasizing the HER2 functions in cancerous cells and their importance. During our research, we used the PUBMED database and analyzed scientific journals. From this research, it was attained that further research needs to be done in order to test the accuracy of HER2 diagnosis through Immunohistochemistry and Fluorescence in Situ Hybridization.  

Introduction: 

According to 2021 cancer statistics, there has been a report of 281,550 new cases of people who have been diagnosed with breast cancer(Cancer of the Breast (Female) - Cancer Stat Facts, 2021). When treating individuals, researchers pay close attention to biomarkers in cancerous cells. Biomarkers are “Genes, proteins, or other substances that can provide information about cancer”(Biomarker Testing for Cancer Treatment). Testing for biomarkers in cancerous cells can aid in choosing the appropriate approach to treatment. 

Methods:  

In this research report, we analyzed data in scientific databases such as PubMed and NIH. Through examining scientific journals, we were able to understand key biomarkers and their link to disease. 

Results:  

Key Biomarkers: 

Among many biomarkers of breast cancer, Estrogen Receptors (ER), Progesterone Receptors (PR), and the Human Epidermal Growth Factor Receptor 2 (HER2) are key ones that have been studied and emphasized in research often. Each of these receptors have their own roles when they are functioning in normality, but when their functions are overused or overexpressed, they play a major role in breast cancer. Gene overexpression, which causes elevated production of proteins, is strongly linked to cancer. 

Functions:  

There are two types of ER biomarkers, ERbeta and ERalpha; both are encoded by different genes and produce different proteins. Estrogens bind to ER, which is a protein inside of cells. This complex will then bind to regulatory proteins. Regulatory proteins, along with the ER and estrogen, define which genes are to be repressed and expressed when creating other proteins. However, according to the NIH, because estrogen can move rather quickly, at times, it would approach the regulatory proteins without needing the ER, which activates the increased formation of some chemicals in the cell (Deroo & Korach, 2006). 

Breast cancer occurs when the cells are using too much estrogen. According to researchers, two possible reasons why too much estrogen causes cancer are that binding estrogen and the ER causes the growth of too many mammary cells and that estrogen produces genotoxic chemicals that damage DNA (Deroo & Korach, 2006). 

The general use of the PR is to regulate the female reproductive system, including the mammary tissues. Similar to the ER and estrogen, PR regulates gene expression, but it has to directly get attached to what is called the Progesterone Response Element (PRE). Similarly, the ER has to bind to what is called the Estrogen Response Element (ERE). The response elements then attach to specific genes.  

Detections:  

All three of the major biomarkers are tested by using immunohistochemistry on samples derived from breast cancer tissues, which might vary. Immunohistochemistry testing uses antibodies linked to enzymes or fluorescent dyes. When the antibody finds the antigen, the dye is activated, so that the antigen could be spotted and analyzed by researchers. Fluorescence In Situ Hybridization (FISH) is also used to detect HER2 biomarkers. FISH uses specific DNA strands as a probe with a fluorescent dye attached to it. Then, the DNA probe finds a specific gene sequence it matches with, so that the muted sequence could be spotted with the dye.  

Uses:  

Depending on how the biomarkers are classified, they can have different uses. In this paper, the biomarkers will be classified as either prognostic, predictive, or pharmacodynamic. ER, PR, and HER2 are all predicative because they help determine the most effective treatment for patients. HER2 is also prognostic because it can be used to predict the disease outcome on the individual without treatment. None of these are pharmacodynamic because they do not necessarily help with determining the outcomes of drugs and medication used (Iwamoto, 2020). For this project, we chose to focus on HER2 because it is a strong predictive biomarker. In fact, doctors are recommended to always test for HER2 because it can make choosing a treatment path much easier.  

HER2 Biomarkers: 

According to research, HER2, also known as Human Epidermal Growth Factor Receptors 2, is a gene that contributes to the growth of breast cells through producing HER2 proteins. These proteins act as connecting receptors on breast cells that aid in controlling the growth, repair, and division of breast cells (HER2 Status: Tests, Treatments, and More, 2020). In healthy functioning breast cells, the HER2 proteins are controlled, and breast cells grow at a normalized pace. However, when the HER2 gene is mutated, it replicates itself rapidly and the production of HER2 proteins is uncontrolled. The overexpression of HER2 proteins causes uncontrolled growth of breast cancer cells. It has been reported that 20%-30% of breast cancer tumors have high levels of HER2 protein (Davoli, A., Hocevar, B. A., & Brown, T. L. 2010). The rapid amplification of HER2 genes in breast cancer cells is referred to as HER2 Positive Breast Cancer. HER2 Positive Breast Cancers tend to grow rapidly and spread easily. Whereas, Negative HER2 Breast Cancers have slower growth rates and are less likely to spread easily (Breast Cancer HER2 Status | What Is HER2 Status?, n.d.). HER2 Negative Breast Cancer is when there are lower levels of the HER2 proteins in cancerous breast cells. In many studies, it has been noted that HER2-positive breast cancer can transform into HER2-negative breast cancer over time. Breast tumors are usually tested for high levels of HER2 proteins through using immunohistochemistry (IHC) test or fluorescence in situ hybridization (FISH) test. These results of the test help healthcare providers in the process of choosing the best treatment plan for patients.  

Discussion:  

HER 2 was our gene of study because it is an aggressive subtype of breast cancer that is most easily diagnosed. Therefore, it is a key biomarker. Doctors must test for the HER2 biomarkers regardless of the symptoms because if it is detected, it would make it much easier to choose a treatment. According to our research, some immunohistochemistry results might be false-positive, which is a significant problem. The immunochemistry test of some minority breast cancers would not always be associated with FISH amplifications (Arafah, M., Kfoury, H. K., & Zaidi, S. N. 2010). Inaccurate HER2 biomarker test results may interfere with a patient’s treatment plan and recovery. Therefore, it is imperative that scientists put emphasis on continuing the research on key biomarkers in breast cancer. 

 

Glossary: 

  1. Amplification: When a gene copies itself but in multiple replication processes so that there are many copies of one gene(Gene Amplification). 

  1. Antibodies: They attack antigens as a part of the immune system.  

  1. Antigens: A type of pathogens that initiates an immune response. 

  1. Biomarker: “Genes, proteins, or other substances that can provide information about cancer” (Biomarker Testing for Cancer Treatment).  

  1. Fluorescence in Situ Hybridization: A test used to locate specific DNA strands (Fluorescence In Situ Hybridization (FISH)). 

  1. Immunohistochemistry: Tests samples, diagnoses diseases like cancer, and can distinguish between types of cancers through antibody and antigen interactions. (Immunohistochemistry ).  

  1. Overexpression: Overproduction of protein copies that use the specifically expressed gene (Overexpress).  

  1. Proliferative Rate: A measure of how fast the cancerous cells are dividing (Proliferative Index). 

  1. Transcription Factors:  Proteins that transcribe DNA into RNA, such as ER and PR.  

  1. Response Elements: The response elements are binding sites for specific transcription factors, such as PR or ER, which are bonded to a specific portion of genes. 

     

References 

Arafah, M., Kfoury, H. K., & Zaidi, S. N. (2010). HER2/neu Immunostaining in Invasive Breast Cancer: Analysis of False Positive Factors. Oman medical journal, 25(4), 261–263. https://doi.org/10.5001/omj.2010.78. 

Biomarker Testing for Cancer Treatment. National Cancer Institute. https://www.cancer.gov/about-cancer/treatment/types/biomarker-testing-cancer-treatment.  

Deroo, B. J., & Korach, K. S. (2006). Estrogen receptors and human disease. The Journal of clinical investigation, 116(3), 561–570. https://doi.org/10.1172/JCI27987  

Fluorescence In Situ Hybridization (FISH). National Human Genome Research Institute. https://www.genome.gov/genetics-glossary/Fluorescence-In-Situ-Hybridization. 

Gene Amplification. National Human Genome Research Institute. https://www.genome.gov/genetics-glossary/Gene-Amplification.  

Immunohistochemistry. National Cancer Institute. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/immunohistochemistry. 

Iwamoto  T,  Kajiwara  Y,  Zhu  Y,  Iha  S. Biomarkers of neoadjuvant/adjuvant chemotherapy for breast cancer. Chin Clin Oncol 2020;9(3):27. doi: 10.21037/cco.2020.01.06 

Overexpress. National Cancer Institute. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/overexpress.  

Proliferative Index. National Cancer Institute. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/proliferative-index. 

Mitri, Z., Constantine, T., & O'Regan, R. (2012). The HER2 Receptor in Breast Cancer: Pathophysiology, Clinical Use, and New Advances in Therapy. Chemotherapy research and practice, 2012, 743193. https://doi.org/10.1155/2012/743193 

Breast Cancer HER2 Status | What is HER2 Status? (n.d.). American Cancer Society. Retrieved November 26, 2021, from https://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-her2-status.html 

Carney W. P. (2005). HER2 status is an important biomarker in guiding personalized HER2 therapy. Personalized medicine, 2(4), 317–324. https://doi.org/10.2217/17410541.2.4.317 

Dendukuri, N., Khetani, K., McIsaac, M., & Brophy, J. (2007). Testing for HER2-positive breast cancer: a systematic review and cost-effectiveness analysis. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne, 176(10), 1429–1434. https://doi.org/10.1503/cmaj.061011 

Cancer of the Breast (Female) - Cancer Stat Facts. (2021). SEER. Retrieved December 2, 2021, from https://seer.cancer.gov/statfacts/html/breast.html 

Perrier, A., Gligorov, J., Lefèvre, G., & Boissan, M. (2018). The extracellular domain of Her2 in serum as a biomarker of breast cancer. Laboratory investigation; a journal of technical methods and pathology, 98(6), 696–707. https://doi.org/10.1038/s41374-018-0033-8 

Duffy, M. J., Walsh, S., McDermott, E. W., & Crown, J. (2015). Biomarkers in Breast Cancer: Where Are We and Where Are We Going?. Advances in clinical chemistry, 71, 1–23. https://doi.org/10.1016/bs.acc.2015.05.001