Identifying Targetable Immune Vulnerabilities in Young Women's Breast Cancer Liver Metastases
Abstract
Patients diagnosed with breast cancer within 10 years of a completed pregnancy are at approx. 3 fold higher risk of subsequently developing metastatic disease. This increased risk is independent of ER, PR or Her-2 status, and is not observed in age matched breast cancer patients who have never had a child nor in women initially diagnosed during their pregnancy, highlighting an unappreciated role of postpartum reproductive biology in breast cancer metastases in young women. Importantly, the only reported site of increased metastases in postpartum women is the liver. This specificity for liver metastasis is the foundation for proposing that the mammary gland and liver are functionally linked postpartum, leading to increased risk for breast cancer metastasis to the liver. To address this novel hypothesis, we turned to rodent models and identified a previously unreported biology, weaning-induced liver involution. In our rodent models we discovered that like the breast, the liver expands to meet the nutrient and metabolic demands of lactation and upon weaning undergoes a developmental program to return to a pre-pregnant like state through an active tissue remolding process characterized by hepatocyte apoptosis, catabolic metabolism, immune cell influx and ECM remodeling. Further, using our rodent models we found liver involution supports enhanced establishment of metastatic tumors compared to livers of nulliparous hosts. Since programmed cell death is functionally linked to immune tolerance in a variety of biologic contents, we hypothesis that PPBC liver metastases will be characterized by active immune tolerance and responsivity to checkpoint inhibitors.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2021
- Accession Number
- AD1152647
Entities
People
- Pepper J Schedin
Organizations
- Oregon Health & Science University