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Novel Postpartum Liver Biology Has Implications for Breast Cancer Liver Metastasis


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Women diagnosed with breast cancer within 10 years of a completed pregnancy are 2 approximately 3x more likely to develop liver metastases than never-pregnant (nulliparous) patients, even after controlling for prognostic variables. This finding suggests a unique biology in the postpartum liver, a putative pre-metastatic niche, which makes postpartum patients more susceptible to liver metastases. Here we tackle the problem of defining the liver-breast cancer tumor cell niche in models of postpartum breast cancer and explore relevance to women, laying the foundation for rational drug design to treat metastatic BrCa to the liver. In rodent models, we previously reported increased liver size, hepatocyte proliferation, and anabolic metabolism during pregnancy and lactation. Within one week post-weaning, the rodent liver returned to its pre-pregnant size via a coordinated cell death and tissue remodeling process we call liver involution. To explore a potential relationship between liver involution and liver metastasis, we utilized an immune competent murine model of postpartum breast cancer (Aim 1). In this model, liver metastases are induced by portal vein injection of mammary tumor cells into nulliparous or involution hosts. Using two different mammary tumor cell lines, we find that the process of involution supports overt liver metastasis. To investigate if increased metastatic burden in the involuting liver is due to increased tumor cell seeding, the number of tumor cells that extravasated into the liver parenchyma was evaluated overtime. Seeding was not enhanced in involution hosts. Time-course experiments show the metastatic advantage in the postpartum host emerges approximately 2 weeks after tumor cell injection. This time frame is consistent with differential tumor cell clearance via cytotoxic immunity, which we hypothesize differs between nulliparous and involution hosts.



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