Estrogen receptor positive (ER+) breast cancer is the most prevalent subtype of breast cancer in Wisconsin. Importantly, more than 25 percent of ER+ cancers recur at distant sites, or metastasize, even 20 years after initial diagnosis. This makes ER+ breast cancer the primary cause of breast cancer-related deaths in Wisconsin women. The primary goal of this project was to investigate how factors of the tumor microenvironment, such as collagen stiffness and fiber alignment, regulate the spread of cancer cells and promote dormancy. By better understanding ER+ breast cancer recurrence, this project has the potential to improve breast cancer treatment and help reduce future recurrences for patients with ER+ breast cancer.
The Challenge
Breast cancer is the most common cancer in women in Wisconsin with more than 5,300 newly diagnosed cases in 2021 and cases continuing to increase each year. Estrogen receptor positive (ER+) breast cancer is the most prevalent subtype of breast cancer diagnosed across the state of Wisconsin and nationwide. Importantly, more than 25% of ER+ cancers recur at distant sites, or metastasize, even 20 years after initial diagnosis. This makes ER+ breast cancer the primary cause of breast cancer related deaths in Wisconsin women. However, researchers have yet to fully understand how the cancer metastasizes. Specifically, there is a need to understand how ER+ tumor cells escape from the primary tumor and remain dormant for prolonged periods before metastatic recurrence.
Project Goals
The primary goal of this project was to investigate how factors of the tumor microenvironment, such as collagen stiffness and fiber alignment, regulate the spread of cancer cells and promote dormancy. The researchers hypothesized that collagen density and estrogen drive mechanisms of dissemination, promote dormant tumor cells, and facilitate the awakening of ER+ tumor cells in the metastatic environment.
Results
The researchers initiated studies of how collagen density drives early dissemination using two approaches. Using collagen-dense mice, they found a significant increase in circulating tumor cells, suggesting the collagen-dense microenvironment promotes a subpopulation of early lesion cells to disseminate early.
The second approach involved generating ER+ tumors by injecting TC11 cells into wild-type and collagen-dense mice. This led to the discovery that estrogen action in the collagen-dense stroma is a driver of tumor growth. They found that G1 treatment delays tumor initiation and significantly reduces tumor growth rates only in collagen-dense mice. Tumor growth curves suggest that G protein-coupled estrogen receptor activity in cancer-associated fibroblasts is differentially regulated by collagen density and may function as a tumor suppressor.
Lasting Impact
This project continues to be of high importance to the investigator’s research program. The data has been used in a grant proposal to study ZFP-281 as a regulator of both early dissemination and prolonged dormancy phenotypes of non-invasive early lesions of breast cancer. This work has led to new collaborations, including with Dr. Amy Trentham-Deitz (Population Health Sciences, UW–Madison), Dr. Thea Tisty (University of California San Francisco), and Dr. Jean-Philippe Coppe (University of California San Francisco).
The principal investigator has access to a tissue microarray of invasive breast cancer biopsies from 178 patients, accompanied by a rich data set. This will allow them to relate findings to the demographics of Wisconsin to determine whether early dissemination is regulated similarly across breast cancer subtypes and how mammographic density relates. Their results may identify populations at risk for latent metastasis from breast cancer, which would ultimately allow clinicians to provide more informed care decisions.
