Extracellular and Myoepithelial Regulation of DCIS Progression to Invasive Disease
Abstract
Rationale and Objective: Ductal carcinoma in situ (DCIS) lesions are regions of abnormal cells contained within the milk ducts, which may or may not develop to invasive breast cancer (IBC). Advances in screening technology have fueled an exponential rise in the diagnosis of early-stage breast lesions, most commonly DCIS. Most DCIS lesions will not progress to invasive disease, but unfortunately it is not currently possible to prospectively distinguish DCIS lesions that will remain stably indolent from those that will progress to malignant cancers. Consequently, many women with indolent DCIS lesions are being systematically overtreated. Years of studies aimed at improving the fate prediction of DCIS lesions have so far not yielded the anticipated outcomes. Such studies are critically limited by the available models for DCIS. There is currently no ex vivo model that correctly recapitulates the unique structure and morphology of DCIS lesions, including the encapsulating epithelial duct and the stromal matrix. Therefore, the effect of the microenvironment on DCIS progression is understudied. Over a decade ago, understanding how the tumor microenvironment controls tumor progression revolutionized how we understand and treat breast cancer. This project proposes a model that will enable us to study DCIS microenvironment, including the encapsulating epithelial duct, in order to understand what determines the invasive progression of this lesion. Career Goals: My long-term career goal is to become an independent researcher and a leader in the field of mammary gland development and breast cancer, focusing on the earliest stages of tumorigenesis, when the developmental program deviates towards cell transformation and malignancy. I have acquired extensive experience studying mammary gland biology, addressing the interface between normal development and cancer, using existing models as well as developing new ones. This proposed research is an ideal transition project, harnessing my existing expertise in mammary gland developmental biology and deepening my breast cancer background to achieve my career goal. My current position as a trainee in the Kuperwasser lab, a leading lab in breast cancer research as well as normal breast development, and the proximity and close collaboration with the Gupta lab at MIT and clinicians at the Tufts Medical Center, provides a well-rounded and supportive training environment for optimal career development. I am highly confident that this research project and the career development plan will support me in achieving my goal of becoming an independent investigator and leader in the field of breast cancer biology. Applicability and Impact: The proposed research plan will advance our ability to models both DCIS lesions that are likely to remain stably indolent and those that are likely to progress to IBC. These studies have the potential to significantly reduce the overtreatment of women diagnosed with non-life-threatening indolent DCIS, which would reduce healthcare costs associated with cancer treatment and minimize the negative ramifications associated with current treatment approaches to DCIS – which include increased risk of developing secondary cancers due to the DNA-damaging effects of treatment. Importantly, current knowledge not only does not enable us to inform patients of the chances of their specific lesion to progress invasively, but we also are unable to suggest ways to reduce the chance of invasive progression, either by intervention or lifestyle changes. This project aims to change that by creating and utilizing an ex vivo model to study the cell-extrinsic factors that control DCIS progression.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010018
Entities
People
- Gat Rauner
Organizations
- Tufts University School of Medicine
- United States Army