Detection of Breast Cancer Progression through Steroid Receptor Crosstalk Associated with Chromatin Remodeling Events
Abstract
Breast cancer is the leading cause of cancer-related death in women with approximately 40,000 deaths and over 230,000 newly diagnosed cases per year. Currently there are very few reliable diagnostic markers in the clinic. Prognostic markers are an important tool for oncologists as they predict likely outcomes of the disease and appropriate treatment option for each patient. A vast array of women s treatment plans relying largely on the presence or absence of the estrogen receptor (ER) a member of the steroid receptor (SR) family. This receptor mediates the effects of the female sex hormone, estrogen. Currently women who have ER-positive breast cancer are treated with drugs that block the actions of this receptor, preventing the hormone estrogen from fueling the cancer growth. However, a large proportion of women with localized breast cancer and nearly all with advanced disease who receive this treatment become resistant. This means the cancer has found a new mechanism to growth, a number of times still through the ER signaling pathway. Suggesting other factors are involved in mediating ER growth patterns. To date the role other hormones in the female body such as progesterone, glucocorticoids, and androgens play on breast cancer growth and the direct effect they have on ER have been largely overlooked, with a great majority of studies focusing on the estrogen hormone alone. This however does not reflect what we see in the female body with a number of different hormones contributing to all SR signaling pathways. We proposed to investigate the direct role of the progesterone receptor (PR), the glucocorticoid receptor (GR), and the androgen receptor (AR) on ER signaling pathways and the effect they each have alone or in combination on breast cancer progression through a number of genome-wide approaches. This has the overarching potential to lead to identifying different treatment options depending on the direct role PR, GR, or AR plays on the ER-mediated signaling. This method is based on a very recent study in our laboratory where we have shown that activated ER or GR can modulate the genome-wide binding patterns of the pioneer factor FoxA1. This factor has been demonstrated to play a role in mediating breast cancer progression and suggests multiple SRs can mediate the effects of transcription factors, suggesting a potential role for PR, GR, or AR on ER-mediated breast cancer growth. The direct outcomes from these experiments will allow me to continue expanding my research ideas and help us further understand the collaborative network of SRs in breast cancer develop. This will support my overall career goal of becoming an independent researcher with a strong focus on breast cancer research. My long-term goal is to utilize molecular genomics in combination with clinical data to define the direct link between breast cancer progression and dynamic interaction of multiple SRs. It s important to note, that the experiments performed here will not only address the direct role PR, GR, and AR have on ER signaling pathways but also begin to address the role they play alone or in combination with each other in breast cancer in the absence of ER. This will allow me to continue investigating the role of other SRs in breast cancer progression as an independent researcher as well as continue my goals of identifying new targetable pathways in breast cancer not only in ER-positive but also in ER-negative breast cancer. The overarching challenges this research addresses are to (1) identify what drives breast cancer growth; determine how to stop it and (2) conquer the problems of overdiagnosis and overtreatment. The studies proposed will ultimately address both these challenges by identify what other factors are contributing to ER signaling pathways in ER-positive breast cancer. Further, they will allow us to theoretically target these additional factors in combination with current treatments to create more effective opti
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710067
Entities
People
- Erin Swinstead
Organizations
- National Cancer Institute
- United States Army