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Accumulating evidence suggests that breast cancer metastatic progression is modified by germline polymorphism, although specific modifier genes have remained largely undefined. In the current study, we employ the MMTV-PyMT transgenic mouse model and the AKXD panel of recombinant inbred mice to identify AT–rich interactive domain 4B ( Arid4b ; NM_194262) as a breast cancer progression modifier gene. Ectopic expression of  Arid4b  promoted primary tumor growth  in vivo  as well as increased migration and invasion  in vitro , and the phenotype was associated with polymorphisms identified between the AKR/J and DBA/2J alleles as predicted by our genetic analyses. Stable shRNA–mediated knockdown of  Arid4b  caused a significant reduction in pulmonary metastases, validating a role for  Arid4b  as a metastasis modifier gene. ARID4B physically interacts with the breast cancer metastasis suppressor BRMS1, and we detected differential binding of the  Arid4b  alleles to histone deacetylase complex members mSIN3A and mSDS3, suggesting that the mechanism of  Arid4b  action likely involves interactions with chromatin modifying complexes. Downregulation of the conserved  Tpx2  gene network, which is comprised of many factors regulating cell cycle and mitotic spindle biology, was observed concomitant with loss of metastatic efficiency in  Arid4b  knockdown cells. Consistent with our genetic analysis and  in vivo  experiments in our mouse model system,  ARID4B  expression was also an independent predictor of distant metastasis-free survival in breast cancer patients with ER+ tumors. These studies support a causative role of  ARID4B  in metastatic progression of breast cancer.

Allelic Variation and Differential Expression of the mSIN3A Histone Deacetylase Complex Gene Arid4b Promote Mammary Tumor Growth and Metastasis