Novel Postpartum Liver Biology Has Implications for Breast Cancer Liver Metastasis
Abstract
Young breast cancer patients diagnosed postpartum are about three times as likely to die from their disease as non-postpartum patients. Breast cancer deaths are due to spread of breast cancer to other organs in a process called metastasis. To metastasize, tumor cells must accomplish a multistep-step process where tumor cells break away from the primary tumor, enter and survive in the circulation, exit blood vessels and enter a new tissue, survive in this “foreign” tissue environment, and eventually grow into life-threatening metastases. However, for breast cancer patients who progress after treatment, it is thought that their disease had escaped the breast and already seeded itself at other organs at the time of their initial diagnosis. Thus, to reduce breast cancer deaths in these young women, strategies to block tumor cell growth at the metastatic site are considered most promising. From a research perspective, preventing growth of metastatic tumor cells in their new “home” has been challenging because it is not known which interactions between the tumor cell and its new environment are important. Here, we propose to take advantage of a newly discovered postpartum biology to investigate how postpartum breast cancer successfully metastasizes. Somewhat surprisingly, increased breast cancer metastasis is specific to women diagnosed after pregnancy, as women diagnosed during pregnancy have comparable survival rates to nulliparous young patients. Our laboratory was the lead in recognizing that a postpartum diagnosis -- not pregnancy -- increased risk of metastasis and patient death, as well as the first lab to identify an important contributing event: postpartum breast involution. Postpartum breast involution is a physiologically normal process that returns the breast to its pre-pregnant state after pregnancy if a woman does not nurse, or after weaning if she does nurse. Breast involution is characterized by death of the epithelial cells specialized for milk production, an increase in immune cells, and increases in extracellular support cells and proteins in a process that resembles wound healing. In rodent models, we find that postpartum breast involution leads to tumor cell escape from the breast and entry into the blood circulation. However, as described above, metastasis requires not only the escape of tumor cells from the primary tumor, but also eventual survival of these escaped tumor cells at distant organs. In fact, compelling data show that the growth of escaped tumor cells at metastatic sites is a rare event, with the vast majority of tumor cells dying once they reach the secondary site. Thus, we hypothesized that tumor cells escaping the mammary gland during involution may survive better at distant sites because the distant sites provide a better “home” in a postpartum compared to a non-postpartum patient. For this hypothesis to be true, organs besides the breast must be different between postpartum and nulliparous women -- a question that had not been previously posed. Following this lead, we discovered that the rodent liver involutes after weaning through a cell death process that removes unneeded liver cells that contributed nutrients for milk production. We also showed that liver involution supports metastatic growth of breast tumor cells. A prediction of our studies is that postpartum breast cancer patients would have high rates of liver metastases compared to nulliparous patients. To address this question, we developed a multi-institutional young women’s breast cancer cohort comprised of ~700 women with complete pregnancy histories and sites of metastasis data. Postpartum patients were almost three times as likely to develop liver metastases compared to nulliparous patients. Further, we found that this increase in liver metastasis was primarily responsible for the overall increased death observed in postpartum patients. As such, we identify the lack of understanding of postpartum liver b
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810086
Entities
People
- Pepper J Schedin
Organizations
- Oregon Health & Science University
- United States Army