A 3D Bioprinted Model of Premalignant Breast Disease
Abstract
Advances in the diagnosis and treatment of breast cancer have resulted in decreased mortality from the disease. The improved survival is due to basic, translational, and clinical research that has led to better diagnosis (e.g., mammography screening) and treatment (e.g., hormonal and chemotherapies). Basic and translational science requires laboratory models of breast cancer, such as breast cancer cell lines. These cell lines grow continuously, and the most studied cell line (MCF-7) is generally regarded as one of the critical elements in the development and success of hormonal agents blocking estrogen receptor such as tamoxifen. While many models exist for invasive breast cancer, this proposal addresses the gap in models of non-invasive premalignant ductal carcinoma in situ (DCIS), which lacks any in vitro models and thus remains understudied. While treatments for invasive breast cancer have been continually refined and personalized over the last 30 years, DCIS remains overdiagnosed and overtreated. Improvements in screening mammography have resulted in earlier detection of invasive breast cancer; however, this is associated with an increase in the detection of non-invasive (premalignant) breast cancer. There is great controversy over non-invasive breast cancer, with some suggesting that it shouldn t even be called cancer. This is because the majority of non-invasive lesions will not progress to invasive disease and if left untreated may not provide any harm. Unfortunately, nearly all women diagnosed with DCIS undergo surgery with or without additional therapy (e.g., radiotherapy and/or endocrine therapy). The majority of these treatments are unnecessary and many carry toxicities; for example, radiation therapy is associated with increased risk of radiation-induced sarcoma. The well-recognized overdiagnosis and overtreatment of DCIS a personal tragedy, a societal travesty, and a drain on healthcare resources. It is clear that more research is required to identify the minority of DCIS lesions that will progress to invasive disease and thus require treatment and the majority that are indolent and can be left untreated. Unfortunately, there are no cell lines derived from primary DCIS lesions, which is an incredible hindrance for the field. We have recently isolated the first primary human DCIS cell lines. However, it isn t simply the cells that are required, but an appropriate way to grow them. DCIS lesions grow inside the ducts of the human breast. Growing them on a plastic dish in the laboratory doesn t replicate the growth in the human breast. We intend to fundamentally transform research on DCIS by generating the first 3D model of DCIS growth in vitro. We will collaborate with bioengineers at Carnegie Mellon University and use state-of-the-art 3D bioprinting to print a breast ductal system in the laboratory, and then grow DCIS cells in the printed duct. A simple proof-of-concept experiment has shown that we can print a replica of a mouse ductal system. In this way, we will then be able to create a unique model to study why some DCIS progress to invasion and why some remain indolent. Genes involved in progression may serve as biomarkers of progression and the need to treat DCIS. This work is basic science and doesn t have immediate clinical application; however, this research is critical to understanding DCIS and then reducing overdiagnosis and overtreatment. Over 60,000 women are diagnosed with non-invasive in situ disease each year. The majority of these women undergo unnecessary treatment. If we can identify genes that cause progression and can then use them to identify the minority of DCIS that are likely to progress, then we can reduce overtreatment for the majority of women. We expect that at the end of the project we will have a suitable in vitro model for study and preliminary data on why some DCIS progress. We will make the model available to all researchers to speed up the research
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610018
Entities
People
- Elizabeth Catherine Firestone
Organizations
- Massachusetts Institute of Technology
- United States Army