Identifying Targetable Immune Vulnerabilities in Young Women s Breast Cancer Liver Metastases
Abstract
Currently, there is no cure for breast cancers that move from the breast to other parts of the body, which is called metastatic breast cancer. Breast cancers that spread to the liver is essentially 100% deadly. Current approved treatments for breast cancer that has spread to the liver includes chemotherapy, hormone treatment, radiation, and surgery. These treatments result in an average survival of less than 14 months after diagnosis and a 3-year survival rate of only 13.5%. These outcomes highlight the fact that the current standard of care for women living with liver metastases is focused on symptom management and the goal of extending life by the measure of months. In this application, we will address the overarching challenge to revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival for breast cancer patients with liver metastasis. Specifically, we will target a population of breast cancer patients that our data strongly suggests will respond well to personalized therapy. These patients are those whose initial breast cancer diagnoses that occurred within 10 years of child birth and are known as postpartum breast cancer patients. The early years after childbirth is a known period of increased breast cancer risk in women. Importantly, postpartum breast cancer patients are approximately three times more likely to have their breast cancer spread to their liver compared to women diagnosed outside of this 10-year postpartum window. Postpartum breast cancer is a significant problem, as we estimate that it accounts for about 50% of all women below the age of 45 diagnosed with breast cancer, which is about 15,000 women a year in the U.S. alone and 160,000 worldwide. To explain why breast cancer patients within 10 years of a recent pregnancy are more likely to be diagnosed with liver metastasis, we investigated reproductive biology that might impact the liver. We hypothesized that there is a functional link between the liver and the breast during pregnancy and lactation that transforms the liver into rich “soil” for breast cancer growth. In support of this hypothesis, in studies of mice we found that the mammary gland (a name for the organ that produces milk in the human breast and other mammals) and the liver both get larger during pregnancy. We know that the mammary gland grows during pregnancy to prepare for milk production, but an expansion in the liver during pregnancy was not previously known to occur. Additionally, at weaning, when milk production ends, the mammary gland and the liver both returned to pre-pregnant sizes. This shrinking process is called weaning-induced involution. In the breast, weaning-induced involution is known to make it easier for breast cancer to take root and grow in the breast tissue. Similarly, we find in mice that liver involution promotes tumor growth in the liver. We hypothesize that biology specific to weaning-induced liver involution is what drives the observed increased rate of liver metastases in postpartum breast cancer patients. Encouragingly, experiments in mice show that the attributes of mammary gland involution that benefit breast cancer tumors can be treated with targeted immunotherapy. Similarly, we believe that we can target breast cancer tumor growth in the liver in the same way. To develop an immunotherapy treatment strategy for breast cancer liver metastasis, we propose the following aims: Aim 1: Define the types of immune cells active in healthy, tumor-free involuting rodent livers: This will tell us more about how the biology of involution changes the immune state of the liver and if these changes explain the observed increased breast cancer metastasis to the liver. Aim 2: Identify immune cells active present in breast cancer in the liver and determine whether these immune cell populations are different in postpartum and non-postpartum liver metastases. We will ask this question in b
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010465
Entities
People
- Pepper J Schedin
Organizations
- Oregon Health & Science University
- United States Army