Neomorphic Cell-Cell Adhesome Reprogramming Facilitates Metastasis of ESR1-Mutant Breast Cancer
Abstract
Breast cancer is the most common cancer in women, and despite tremendous improvements in diagnosis and treatment, 40,000 women (and men) die of the disease each year. The estrogen receptor (ER/ESR1) is expressed in the majority of breast cancers and is a major driver of breast cancer development and progression, ultimately leading to metastases and death from the disease. Hormonal therapy targeting ER, known as endocrine or antiestrogen therapy, is one of the most efficacious and least toxic treatments for ER-positive (ER+) breast cancer and has significantly reduced breast cancer mortality for over a century. However, lack of treatment response, i.e., resistance, is a major clinical problem. Many patients initially respond to endocrine therapy but later relapse with aggressive resistant disease. Even when breast cancers become resistant to current endocrine therapies, they often remain dependent on ER itself, thus warranting further research into the role of ER in advanced breast cancer. Endocrine-resistant breast cancer is an urgent clinical and socio-economical challenge. A deeper understanding of the mechanisms of endocrine resistance and the metastatic spread of breast cancer is needed. Studies have shown that the ER gene is mutated in ~20%-30% of advanced breast cancers, which renders them resistant to traditional endocrine therapies. These mutations, which change the behavior of ER, have been shown to lead to drug resistance and to ligand independence; that is, the mutated ER does not respond to normal cellular cues, it remains active at all times and drives the cells to continue to divide and allows the tumor to grow and spread. Recent research from our group and others has demonstrated that the ER mutations in advanced breast cancer not only lead to endocrine resistance (i.e., resistance to hormonal therapy) but may also confer additional properties to the cancer cells that allow them to spread more easily within the body. Our data using robust laboratory models suggests that specific ER mutations may confer special abilities to the cancer cells that increase their capacity to metastasize. Our data indicates that these mutations allow the cells to become more “sticky,” forming clusters or groups of cancer cells, which present an advantage as they leave the primary tumor and spread. We hypothesize that these cell clusters have a greater ability to survive in the bloodstream than single cancer cells and are more likely to lead to tumors in other parts of the body such as the liver, lung, and bone. We aim to understand how these mutations lead to the increased “stickiness,” or cell-cell adhesion, of these cells and whether targeting this property with drugs can suppress metastatic spread. We propose to assess the cell adhesion phenotype using novel imaging techniques both in cell culture and in live mouse models of metastatic breast cancer to provide further evidence of the increased capacity of ER mutant cells to metastasize. Using cutting-edge sequencing technologies, we will aim to better understand the mechanism of increased cell adhesion and metastasis. We will use targeted drugs and gene manipulation techniques to reduce the increased cell adhesion of mutant ER cells to understand the contributions of specific proteins and to identify and validate new drug targets. Following drug target identification, we will test potential therapies in mouse models for their ability to reduce metastatic spread. Since a number of agents active in inhibiting cell adhesion have already undergone testing in humans such as carbenoxolone and mefloquine, we envisage rapid clinical repurposing of existing drugs following preclinical efficacy. Finally, we will assess blood (i.e., “liquid biopsies”) from patients (with and without ER mutation) to look for clustering of cancer cells in the bloodstream and assess if this occurs more readily in patients with mutant ER. This work is both basic and translational sci
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910499
Entities
People
- Steffi Oesterreich
Organizations
- United States Army
- University of Pittsburgh