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Immune Milieu Established by Postpartum Liver Involution Promotes Breast Cancer Liver Metastasis

Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA
Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97201, USA
Young Women’s Breast Cancer Translational Program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Author to whom correspondence should be addressed.
Academic Editors: Lingzhi Wang and Qiang Jeremy Wen
Cancers 2021, 13(7), 1698;
Received: 28 February 2021 / Revised: 30 March 2021 / Accepted: 2 April 2021 / Published: 3 April 2021
(This article belongs to the Special Issue Targeting Cancer Metastasis)
Cancer becomes lethal when it metastasizes to secondary sites, and for breast cancer metastasis to the liver is a serious clinical problem. Liver metastasis is promoted, in part, by changes to the liver environment, resulting in the formation of a metastatic niche that supports circulating tumor cells. Understanding how the liver niche support breast cancer cells may lead to development of treatments for patients with metastatic breast cancer. Here, we report that the developmentally regulated process of weaning-induced liver involution increases liver metastasis in cancer cells with otherwise low metastatic potential. Increased metastasis associates with unique immunological properties in the involuting liver, including reduced ability to activate T cells required for tumor cell clearance. These data establish physiologic liver involution as a model to understand the liver metastatic niche and suggest future research into whether the immune milieu identified in the involuting liver could be targeted to treat metastases more generally.
In rodents, we identified a physiologic process within the normal liver that creates a pre-metastatic niche. This physiology is weaning-induced liver involution, characterized by hepatocyte cell death, immune influx, and extracellular matrix remodeling. Here, using weaning-induced liver involution as a model of a physiologically regulated pro-metastatic niche, we investigate how liver involution supports breast cancer metastasis. Liver metastases were induced in BALB/c immune competent hosts by portal vein injection of D2OR (low metastatic) or D2A1 (high metastatic) mouse mammary tumor cells. Tumor incidence and multiplicity increased in involution hosts with no evidence of a proliferation advantage. D2OR tumor cell extravasation, seeding, and early survival were not enhanced in the involuting group compared to the nulliparous group. Rather, the involution metastatic advantage was observed at 14 days post tumor cell injection. This metastatic advantage associated with induction of immune tolerance in the involution host liver, reproductive state dependent intra-tumoral immune composition, and CD8-dependent suppression of metastases in nulliparous hosts. Our findings suggest that the normal postpartum liver is in an immune suppressed state, which can provide a pro-metastatic advantage to circulating breast cancer cells. Potential relevance to women is suggested as a postpartum diagnosis of breast cancer is an independent predictor of liver metastasis. View Full-Text
Keywords: metastatic niche; liver metastasis; breast cancer; liver involution metastatic niche; liver metastasis; breast cancer; liver involution
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MDPI and ACS Style

Bartlett, A.Q.; Pennock, N.D.; Klug, A.; Schedin, P. Immune Milieu Established by Postpartum Liver Involution Promotes Breast Cancer Liver Metastasis. Cancers 2021, 13, 1698.

AMA Style

Bartlett AQ, Pennock ND, Klug A, Schedin P. Immune Milieu Established by Postpartum Liver Involution Promotes Breast Cancer Liver Metastasis. Cancers. 2021; 13(7):1698.

Chicago/Turabian Style

Bartlett, Alexandra Q., Nathan D. Pennock, Alex Klug, and Pepper Schedin. 2021. "Immune Milieu Established by Postpartum Liver Involution Promotes Breast Cancer Liver Metastasis" Cancers 13, no. 7: 1698.

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