Breast and Endocrine Surgery
- Promote practical application of a prognosis and drug sensitivity prediction model based on gene expression profiles
- Promote practical application of an axillary lymph node metastasis prediction model
- Develop sentinel lymph node metastasis prediction method
- Develop a new margin diagnostic method using azide probe
- Identify target genes and develop treatment method using genome information
Towards personalized medicine: development of highly accurate, state-of-the-art molecular diagnostic methods for prognosis and drug susceptibility in breast cancer
The laboratory conducts clinical work and basic research on breast cancer, which is the most prevalent cancer in women. Thus, it is essential to develop a molecular diagnostic method that can accurately diagnose specific molecular patterns of breast cancer in order to provide the best medical care. To this end, the lab is working on the development of novel molecular diagnostic methods.
In order to administer an appropriate adjuvant chemotherapy based on the risk of recurrence in individual breast cancer patients, it is critical to develop a diagnostic method for accurate prognosis. The lab has developed and commercialized a 95-gene classifier (95-GC) for prognosis prediction for breast cancer (Curebest 95 GC Breast®, Sysmex Corporation), which analyzes the expression profiles of 95 genes found in breast cancer tissue [1, 2]. Using this method, it is possible to distinguish between high- and low-risk recurrence groups. The prognostic accuracy can be further improved by combining Curebest 95 GC with Oncotype DX.
Because a standardized and accurate method to predict the effectiveness of chemotherapy on breast cancer does not exist, inappropriate chemotherapy has been frequently prescribed. Therefore, the lab developed a chemo-sensitivity prediction method (IRSN 23, Japanese Patent Application No. 14182820.2) based on the analysis of 23 immune related gene expression profiles in breast cancer tissue [3]. Using this method, it is possible to diagnose preoperative chemotherapy failure with high precision. The lab has also developed a high-sensitivity detection method for circulating tumor DNA (ctDNA) to monitor recurrence, One-Step Methylation Specific PCR [4, 5]. In addition to developing more accurate and sensitive ctDNA detection methods using next generation sequencing, the lab is currently working on elucidating mechanisms of hormone and anti-HER2 therapy resistance and improving the OSNA (one-step nucleic acid amplificaiton) method for detection of lymph node metastasis.
The lab is currently planning or carrying out clinical trials to evaluate the utility of these novel molecular diagnostic methods. Finally, the lab strives for excellence in both clinical and research of breast cancer.
Cell Biology and Translational Immunology in Breast Cancer
Plasticity of Breast Cancer Cells
Breast cancer cells usually retain their epithelial features. However, cancer cells can acquire non-epithelial characteristics (i.e. plasticity) due to the influence of their microenvironment. Controlling these characteristics may suppress the progression of breast cancer because this phenomenon is closely related to tumor growth, metastasis, and treatment resistance. We have clarified the mechanism of plasticity and identified small molecule compounds that inhibited the plasticity of breast cancer cells. For example, we showed that a cytokine, TGF-β, promoted the transition of breast cancer cells into stem cells, and that a SMAD3 inhibitor blocked the transition of breast cancer cells to cancer stem cells [6]. We also demonstrated that the malignant progression of breast cancer cells was related to the transition to endothelial-like cells (vasculogenic mimicry) in the presence of angiogenic cytokines such as vascular endothelial growth factor (VEGF) [7] (Figure). We now religiously investigate the inhibitors targeting breast cancer plasticity, which may lead to the development of novel molecular-targeted therapies.
The Role of Humoral Immunity in Breast Cancer
Not many breast cancer patients benefit from cellular immunity against breast cancer, even though cellular immunity plays an important role in cancer immunity. We demonstrated that patients with high serum levels of anti-HER2 autoantibodies have a better prognosis [8]. Based on this finding, we further demonstrated that humoral immunity was enhanced in the microenvironment of breast cancer in patients with high serum levels of anti-HER2 autoantibodies (Sato et al., submitted). Therefore, we hypothesize that humoral immunity plays an essential role in antitumor immunity in patients with breast cancer. Furthermore, we are now trying to identify the immune cells that enhance humoral immunity in breast cancer microenvironments to better understand the relationship between humoral immunity and breast cancer. We hope that our investigation will lead to developing a novel immunotherapy against breast cancer.
Development of Rapid Intraoperative Diagnosis of Mastectomy Margins in Breast Cancer Surgery
Today, breast-conserving surgery is widely used for the treatment of breast cancer. As a result, finding exactly where a tumor ends and where the healthy tissue begins is an important—but difficult—task for cancer surgeons. The most popular method for finding boundaries (intraoperative margin management) is frozen section analysis but it is time-consuming and labor-intensive. We have developed a way to sensitively, selectively, and quickly detect surgical margins by using a “Click-to-Sense” Acrolein probe that conjugates with the components of live breast cancer cells. Acrolein is a highly toxic chemical that is generated in tumor cells and other cells undergoing oxidative stress. We have developed a new rapid and inexpensive way to accurately and quickly detect the margins between cancer and non-cancerous tissue during breast surgery. Their system is noteworthy in that it can detect the morphology of the cells, differentiating between cells that are more or less dangerous. Currently, this method seems to have a potential to be a great advance for breast-conserving breast cancer surgery in combination with artificial intelligence (AI) diagnostic imaging technology.
New Diagnostic Technique to Quickly Detected Live Breast Cancer Tissues for Intraoperative Resection
【References】
- Naoi et al. Breast Cancer Res Treat 128: 633-641, 2011.
- Oshima et al. Cancer Lett 307: 149-157, 2013.
- Sota et al. Ann Oncol 25: 100-106, 2014.
- Yamamoto et al. Breast Cancer Res Treat 132: 165-173, 2012.
- Takahashi et al. Clinical Breast Cancer 17(1):61-69, 2016.
- Chihara et al., Breast Cancer Res Treat. 166: 55-68, 2017.
- Hori et al., Breast Cancer Res. 21: 88, 2019.
- Tabuchi et al., Breast Cancer Res Treat. 157: 55-63, 2016.
