Abstract 4817: Protein aggregation promotes HSF1 activity enhancing cell survival during metastatic breast cancer colonization

Abstract

Abstract Breast cancer is the most commonly diagnosed cancer in women and is the second leading cause of cancer-related deaths in women. Approximately 20-30% of patients will develop metastases and metastasis is responsible for greater than 90% of breast cancer deaths. Metastasis is a complex process in which the cells combat many forces to survive and spread to different areas of the body. Metastatic colonization is the rate-limiting step of metastasis and is an inefficient process in which most cells die and only a small fraction of those that survive can form metastases. We have previously shown that heat shock factor 1 (HSF1) promoted epithelial-to-mesenchymal transition (EMT) and the breast cancer stem-like population, potentially linking HSF1 to metastasis. Utilizing an HSF1 gene expression signature that assesses HSF1 transcriptional activity, we further found that patients with high HSF1 activity have significantly worse metastasis-free survival. The physiological function of HSF1 is the master regulator of the heat shock response wherein it upregulates chaperone proteins under stress conditions. Because of these functions and the fact that the process of metastatic colonization is known to involve the stem cell population and incur external stressors, we hypothesized that HSF1 may function in metastatic colonization. To test this, we subjected human breast cancer MDA- MB-231 cells with or without HSF1 knockdown to intracardiac injections in nude mice. This model injects cells directly into the circulation allowing for assessment of metastatic tumor formation in which the major barrier will be metastatic colonization. Mice receiving cells with knockdown of HSF1 had a significantly reduced metastatic burden, indicating HSF1 is necessary for the completion of metastasis and colonization. Consistent with these findings, bone metastatic tumor specimens from patients show increased HSF1 activation compared to their matched primary breast tumors. The mechanism by which HSF1 enables metastatic colonization is unknown. Metastatic colonization likely requires at least two stages that include tumor initiation (or early colonization) characterized by the seeding of a tumor followed by tumor expansion (or late colonization) characterized by rapid proliferation and an increase in tumor size. We observed increased protein amyloid aggregates that correlate with an increase in HSF1 activity during mammosphere formation, suggesting that colonization induces aggregation leading to HSF1 activation that promotes a cell survival response. Overall, my results indicate that HSF1 activity increased during breast cancer metastasis and HSF1 is necessary for colonization. Going forward, I want to understand what controls HSF1 activation during metastasis, which I hypothesize that protein aggregation is increased leading to HSF1 activation. Citation Format: Natasha Hockaden, Gabi Leriger, John Wang, Haimanti Ray, Richard Carpenter. Protein aggregation promotes HSF1 activity enhancing cell survival during metastatic breast cancer colonization. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4817.