ECTS Abstracts (2015) 1 P138

HIF signalling in skeletal progenitors promotes breast cancer growth and metastasis through systemic production of CXCL12

Claire-Sophie Devignes1, Audrey Brenot2, Amy-Jo Casbon2, Audrey Devillers1, Ying Yu2, Zena Werb2 & Sylvain Provot1

1INSERM U1132, Hôpital Lariboisière, Paris, Ile-de-France, France; 2UCSF, Department of Anatomy, San Francisco, California, USA.

High bone mineral density (BMD) has long been associated with increased risk of breast cancer. Conversely, low bone mass has been correlated with lower risk of breast cancer. Although BMD was initially thought to reflect a cumulative exposure to oestrogens, recent clinical trials demonstrated that high bone mass correlates with elevated breast cancer incidence independently of reproductive correlates, endogenous and exogenous exposure to oestrogen. However, the biological mechanism linking bone mass and the risk of breast cancer is unknown. Our objective was to investigate the role of the osteoblastic lineage in breast cancer, using transgenic mice presenting increased or decreased bone mass (all animal protocols were approved by an animal ethics committee). Here we show that osteoprogenitor cells, targeted by Osterix driven Cre-recombinase, exert a systemic control of breast cancer growth and metastasis. Deletion of the tumour suppressor gene von Hippel Lindau (Vhlh) specifically in mouse osteoprogenitors (Osx/Vhlhfl/fl), which results in increased protein level of the Hypoxia-Inducible Factor-1alpha (Hif-1alpha) in these cells, led to increased bone mass, and increased mammary tumour growth and metastasis. Conversely, deletion of Hif-1alpha in osteoprogenitors (Osx/Hif-1alphafl/fl) decreased bone mass, and dampened mammary tumour growth and metastasis. We found that changes in the bone microenvironment are associated with changes in the plasmatic levels of the chemokine C-X-C motif ligand 12 (CXCL12). Pharmacological inhibition of the CXCL12-CXCR4 pathway abolished increased primary tumour growth and dissemination in Osx/Vhlhfl/fl mice. Therefore, skeletal dysfunction alters tumorigenesis beyond the bone microenvironment. Our results provide a mechanistic explanation as for why high bone mass is linked to increased risk of breast cancer, and support the notion that the skeleton is an important organ of the tumour macroenvironment. They also indicate that drugs affecting bone homeostasis may have important consequences in breast cancer.

Disclosure: The authors declared no competing interests. This works was supported by the University of California Academic Senate, the Association Le cancer du Sein parlons-en, the INSERM grant #RSE11013HSA, and by the ARC grant #RAC11002HSA, to S.P.

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