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Nat Cell Biol. 2016 Oct;18(10):1078-1089. doi: 10.1038/ncb3408. Epub 2016 Sep 19.

Induction of LIFR confers a dormancy phenotype in breast cancer cells disseminated to the bone marrow.

Author information

1
Department of Radiation Oncology, Division of Radiation and Cancer Biology, Stanford University, Stanford, California 94305, USA.
2
Department of Veterans Affairs: Tennessee Valley Healthcare System (VISN 9), Nashville, Tennessee 37212, USA.
3
Department of Medicine, Division of Clinical Pharmacology, Nashville, Tennessee 37232, USA.
4
Vanderbilt Center for Bone Biology, Nashville, Tennessee 37232, USA.
5
Department of Medicine, Division of Endocrinology, Stanford University, Stanford, California 94305, USA.

Abstract

Breast cancer cells frequently home to the bone marrow, where they may enter a dormant state before forming a bone metastasis. Several members of the interleukin-6 (IL-6) cytokine family are implicated in breast cancer bone colonization, but the role for the IL-6 cytokine leukaemia inhibitory factor (LIF) in this process is unknown. We tested the hypothesis that LIF provides a pro-dormancy signal to breast cancer cells in the bone. In breast cancer patients, LIF receptor (LIFR) levels are lower with bone metastases and are significantly and inversely correlated with patient outcome and hypoxia gene activity. Hypoxia also reduces the LIFR:STAT3:SOCS3 signalling pathway in breast cancer cells. Loss of the LIFR or STAT3 enables otherwise dormant breast cancer cells to downregulate dormancy-, quiescence- and cancer stem cell-associated genes, and to proliferate in and specifically colonize the bone, suggesting that LIFR:STAT3 signalling confers a dormancy phenotype in breast cancer cells disseminated to bone.

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