De Wilde, E. | Search bioRxiv

bioRxiv2024

Reproductive state controls transcription in the murine liver, with implications for breast cancer liver metastasis

Liver biology is functionally linked to lactation, as liver size and metabolic output increase during lactation to support synthesis of breast milk. Upon weaning, the rodent liver returns to baseline homeostasis via hepatocyte cell death, in a process considered liver involution. To explore liver biology changes across a lactation-wean cycle, we employed transcriptomic profiling. We identified elevated hepatocyte proliferation and anabolic metabolism gene signatures during lactation, consistent with the liver being a major producer of substrates needed for milk production. Rapid loss of these capacities upon weaning correlated with catabolic metabolism, lysosomal-mediated cell death, and an influx of immune suppressive cells. Furthermore, we identified that the transcriptional profiles associated with liver involution share similarities with the gene expression patterns of liver pre-metastatic niches. This work identifies features of reproductive control of liver biology that sets a foundation for better understanding the potential role of the liver in maternal health.

cancer biology↗

bioRxiv2024

Altered liver metabolism post-wean abolishes efficacy of vitamin D for breast cancer prevention in a mouse model

Young women have increased risk of vitamin D deficiency, which may increase breast cancer incidence. Here, we assessed the anti-cancer efficacy of vitamin D in mouse models of young-onset breast cancer. In never-pregnant mice, vitamin D supplementation increased serum 25(OH)D and hepatic 1,25(OH)2D3, reduced tumor size, and associated with anti-tumor immunity. These anti-tumor effects were not replicated in a mouse model of postpartum breast cancer, where hepatic metabolism of vitamin D was suppressed post-wean, which resulted in deficient serum 25(OH)D and reduced hepatic 1,25(OH)2D3. Treatment with active 1,25(OH)2D3 induced hypercalcemia exclusively in post-wean mice, highlighting metabolic imbalance post-wean. RNAseq revealed suppressed CYP450 expression postpartum. In sum, we provide evidence that vitamin D anti-tumor activity is mediated through immunomodulatory mechanisms and is ineffective in the post-wean window due to altered hepatic metabolism. These findings have implications for suppressed xenobiotic metabolism in postpartum women beyond vitamin D. Statement of SignificanceIn a rodent model of postpartum breast cancer, weaning suppresses hepatic CYP450 activity and renders vitamin D supplementation ineffective, with implications for xenobiotic drug efficacy and safety. A tailored approach to therapy based on reproductive history is crucial for young breast cancer patients, and for healthcare strategies for postpartum women.

cancer biology↗