Globally each year, more than 600,000 women succumb to deadly breast cancer—the most common cancer affecting women. While individual or combined effects of lifestyle and environmental factors contribute to the development of breast cancer in a large percentage of the female population, the formation of malignancy is usually associated with genetic factors. For example, BRCA1 and BRCA2 are two genes that impact a person's chances of developing breast cancer. Under normal conditions, the protein products of these genes help in repairing DNA damages, thereby reducing the chances of uncontrolled cell growth and tumor development. Any “mutation” or cellular level abnormalities that hinder the functioning of the BRCA genes, thus, predispose the person to a higher chance of developing breast cancer.
As such, for decades, researchers have been focusing on deciphering the role of BRCA genes and the cellular components associated with BRCA1 and BRCA2 proteins to understand the progression of breast cancer, and design appropriate targeted therapeutics to prevent and treat the disease. Now, a group of collaborating researchers from Japan and the USA has successfully identified a protein from the BRCA-associated cellular machinery that plays a critical role in the progression of breast cancer. The prominent researchers who were part of this research project were Kazuhiko Kuwahara (Fujita Health University School of Medicine, Japan), Naomi Gondo (Division of Immunology, Aichi Cancer Center Research Institute, Nagoya, Japan), Yasuhiro Sakai (Department of Joint Research laboratory of Clinical Medicine, Fujita Health University School of Medicine, Toyoake, Japan), Zhenhuan Zhang (Radiation Oncology Department, University of Florida, Gainesville, FL), and Andri Rezano (Department of Biomedical Sciences, Division of Cell Biology, Faculty of Medicine, Universitas Padjadjaran, West Java, Indonesia). The findings of the study, recently published in Laboratory Investigation , offer important leads for developing targeted therapy for the fatal disease, too.
In their study, the researchers started by looking closely at a protein complex called TRanscription–EXport-2 (TREX-2), which is involved in the transcription and export of mRNA from the nucleus. The complex is made up of several proteins, such as GANP, PCID2, DSS1, and centrin ¾, and as per earlier reports, aberrant expression of some of these proteins leads to DNA damage that results in tumor formation. Dr. Kuwahara, the corresponding author of the study, explains what made them look into TREX-2 complex proteins, “ Earlier, we observed GANP-deficiency was closely associated with breast carcinogenesis. We were therefore interested to look into other protein components of the TREX-2 complex for their possible association with breast cancer .” Based on available published information, they focused on DSS1, a protein that is known to be associated with the stabilization of the BRCA2 protein in human cell lines.
To test their assumptions, the researchers conducted a series of studies that started with checking the expression levels of various TREX-2 complex proteins, including DSS1, in breast cancer tissues, followed by cellular level experiments. They found that the DSS1 protein expression was higher in human breast carcinoma tissues than in normal tissues. In contrast, the expression of PCID2 protein was normal in malignant tissues. They also found that low DSS1 expression is associated with longer survival time in patients. Interestingly, breast cancer cells with diminished DSS1 levels were more sensitive to standard anti-cancer drugs DXR and PTX, while a high level of DSS1 made the breast cancer cells resistant to these therapeutic agents.
The findings marked a breakthrough for breast cancer treatment research. Dr. Kuwahara summarizes, “ Strong side effects of anti-cancer therapeutics add to the suffering of the patients and complicates the treatment modalities. Our research suggests depleting the DSS1 protein from breast cancer cells may make the cells chemosensitive, that is more responsive to lower doses of anti-cancer drugs, which means the chances of drug-induced adverse effects in patients with breast cancer will be reduced by this technique .”
The promising result of this study generates hope for an era of safer chemotherapy, in the near future, for patients suffering from breast cancer.
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Reference
Title of original paper: Increased chemosensitivity via BRCA2-independent DNA damage in DSS1- and PCID2-depleted breast carcinomas
Journal: Laboratory Investigation
DOI: https://doi.org/10.1038/s41374-021-00613-6
About Fujita Health University
Fujita Health University is a private university situated in Toyoake, Aichi, Japan. It was founded in 1964 and houses one of the largest teaching university hospitals in Japan in terms of the number of beds. With over 900 faculty members, the university is committed to providing various academic opportunities to students internationally. Fujita Health University has been ranked eighth among all universities and second among all private universities in Japan in the 2020 Times Higher Education (THE) World University Rankings. THE University Impact Rankings 2019 visualized university initiatives for sustainable development goals (SDGs). For the “good health and well-being” SDG, Fujita Health University was ranked second among all universities and number one among private universities in Japan. The university will also be the first Japanese university to host the "THE Asia Universities Summit" in June 2021. The university’s founding philosophy is “Our creativity for the people (DOKUSOU-ICHIRI),” which reflects the belief that, as with the university’s alumni and alumnae, current students also unlock their future by leveraging their creativity.
Website: https://www.fujita-hu.ac.jp/en/index.html
About Dr. Kazuhiko Kuwahara from Fujita Health University
Dr. Kazuhiko Kuwahara is a Senior Associate Professor in the Department of Diagnostic Pathology, Fujita Health University, Japan. He earned his MD degree from Saga Medical School in 1989, following which he has continued in his career as a researcher in the field of immunology. His current research focus is developing newer treatment strategies for breast cancer while reducing the side effects associated with chemotherapy. As an expert in the field, Dr. Kuwahara has published 66 research papers in reputed journals.
Funding information
This study was supported by a Grant-in-Aid for challenging Exploratory Research 16K15603 (NG), a Grant-in-Aid for Young Scientists 20K16228 (YS), and Grants-in-Aid for Scientific Research (C) 24590388, 15K10083, and 20K07686 (KK) from the Japan Society for the Promotion of Science; a Grant-in-Aid for Young Scientists from Fujita Health University (YS); and Grants-in-Aid from Aichi Cancer Research Foundation (KK), the 24th General Assembly of the Japanese Association of Medical Sciences (KK), and Aichi Health Promotion Foundation (KK). AR was supported by an Indonesian Directorate General of Higher Education (DIKTI) Scholarship.
Laboratory Investigation
Experimental study
People
Increased chemosensitivity via BRCA2-independent DNA damage in DSS1- and PCID2-depleted breast carcinomas
23-May-2021
The authors declare no competing interests.