PDGFB in Breast Cancer Initiation, Progression, and Metastasis
Abstract
Breast cancer (BC) is a complex disease made even more complicated by the heterogeneous nature of breast tumors, which are comprised not only of cancer cells, but also of non-cancer cells that surround and interweave within the tumor. These non-cancer cells are collectively termed the “tumor microenvironment.” Over the past decade or so, it has become increasingly clear that these non-cancer cells of the tumor microenvironment are not just bystanders in BC, but are also active participants from the beginning of the disease all the way through to the development of metastases at distant sites such as the lung, liver, bone, and brain. The current proposal is focused on the interplay between the tumor cells and the metastatic microenvironment, an area the scientific community knows very little about. Even with major advancements in BC treatment, this year it is expected that 276,480 women in the United States will be diagnosed with BC and 42,170 will die from their disease. This devastatingly high number is almost entirely due to metastatic spread to distant organs. As a biomedical research community, we have an obligation to figure out how BC finds its way to these distant sites that are so completely different from the breast. More importantly, we have a responsibility to turn this acquired knowledge into novel clinical strategies including: (1) the development of new clinical tests that can be used to predict which women are at increased risk for developing metastases and (2) the development of new drugs that can be used to prevent and treat metastatic disease. The experiments described herein will directly address both of these clinical shortcomings. As mentioned above, my laboratory is interested in how the “metastatic microenvironment” responds to BC. If we can identify why BC cells travel to and survive in these distant sites, we can potentially stop the metastases from forming or advancing. Our preliminary research to date has suggested that a specific set of proteins, one expressed by the cancer cell (“PDGFB”) and one expressed by the metastatic microenvironment (“PDGFRbeta”), need to talk to each other for the progression of BC and the development of metastases. We have confirmed these findings clinically by evaluating PDGFB in tumor samples obtained from biopsy or surgical resection within a large cohort of women treated for BC at the Ohio State University (OSU) James Comprehensive Cancer Center. These women have tumors that are either HER2-positive [express the HER2 protein, which means they received standard of care with anti-HER2 therapies (e.g., trastuzumab)] or are triple-negative (meaning their tumors do not express the three known targetable receptors – ER, PR or HER2). This cohort was chosen for our studies because patients with HER2 and “triple-negative” disease have a less favorable prognosis than those with ER/PR+ disease, even with advancements in anti-HER2 therapies. In this OSU patient cohort, high PDGFB in the breast tumor can predict which women will go on to develop brain metastases months or years later. These findings are clinically very relevant because women that are diagnosed with brain metastases have an extremely short life expectancy (average of 10-11 months) compared to women with lung, liver, or bone metastases, which confer life expectancies of 30, 31, and 41 months, respectively. These preliminary findings are supported by decades-old research that high “PDGF” is found in the blood of BC patients whose cancer later returns, compared to low “PDGF” levels in those patients that remain cancer-free. In the current application, I have detailed an experimental strategy that will directly address three of the Breast Cancer Research Program’s Fiscal Year 2020 “Overarching Challenges”. The first part of the application will create new mouse models of high breast “PDGFB” mirroring what is seen in human breast cancer. These models in combination with human xenograft mouse models will allow us to
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110021
Entities
People
- Gina Sizemore
Organizations
- Ohio State University
- United States Army