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Background  Dissemination of breast cancers to the brain is associated with poor patient outcome and limited therapeutic options. In this study we sought to identify novel regulators of brain metastasis by profiling mouse mammary carcinoma cells spontaneously metastasising from the primary tumour in an immunocompetent syngeneic host.    Methods  4T1 mouse mammary carcinoma sublines derived from primary tumours and spontaneous brain and lung metastases in BALB/c mice were subject to genome-wide expression profiling. Two differentially expressed genes,  Id2  and  Aldh3a1 , were validated in in-vivo models using mouse and human cancer cell lines. Clinical relevance was investigated in datasets of breast cancer patients with regards to distant metastasis-free survival and brain metastasis relapse-free survival. The role of bone morphogenetic protein (BMP)7 in regulating  Id2  expression and promoting cell survival was investigated in two-dimensional and three-dimensional in-vitro assays.    Results  In the spontaneous metastasis model, expression of  Id2  and  Aldh3a1  was significantly higher in 4T1 brain-derived sublines compared with sublines from lung metastases or primary tumour. Downregulation of expression impairs the ability of cells to colonise the brain parenchyma whereas ectopic expression in 4T1 and human MDA-MB-231 cells promotes dissemination to the brain following intracardiac inoculation but has no impact on the efficiency of lung colonisation. Both genes are highly expressed in oestrogen receptor (ER)-negative breast cancers and, within this poor prognosis sub-group, increased expression correlates with reduced distant metastasis-free survival.  ID2  expression also associates with reduced brain metastasis relapse-free survival. Mechanistically, BMP7, which is present at significantly higher levels in brain tissue compared with the lungs, upregulates  ID2  expression and, after BMP7 withdrawal, this elevated expression is retained. Finally, we demonstrate that either ectopic expression of  ID2  or BMP7-induced  ID2  expression protects tumour cells from anoikis.    Conclusions  This study identifies  ID2  as a key regulator of breast cancer metastasis to the brain. Our data support a model in which breast cancer cells that have disseminated to the brain upregulate  ID2  expression in response to astrocyte-secreted BMP7 and this serves to support metastatic expansion. Moreover, elevated  ID2  expression identifies breast cancer patients at increased risk of developing metastatic relapse in the brain.    Electronic supplementary material  The online version of this article (10.1186/s13058-018-1093-9) contains supplementary material, which is available to authorized users.

Using an in-vivo syngeneic spontaneous metastasis model identifies ID2 as a promoter of breast cancer colonisation in the brain