Abstract
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.
Highlights
Breast cancer remains the most commonly diagnosed malignancy among women in the United States [1]
Our laboratory’s strategy is to cross genetically defined inbred mouse strains to recapitulate a degree of genetic diversity that is more readily studied. By breeding these panels of inbred mouse crosses to a mouse model of breast cancer, we can identify regions of the genome that correlate with observed phenotypic variation including metastatic density and identify individual candidate genes
This manuscript describes the identification of AT–rich interactive domain 4B (Arid4b) as a candidate gene of interest and the experiments we performed to validate its role in metastasis
Summary
Breast cancer remains the most commonly diagnosed malignancy among women in the United States [1]. Identifying and characterizing metastasis susceptibility genes would provide additional insights into the mechanisms associated with tumor dissemination and growth, leading to better understanding of this complex process and to new targets and strategies for clinical intervention. Due to the complex interactions between inherited factors and somatic mutations in metastatic progression, as well as the genetic complexity of human populations, identification of inherited susceptibility genes directly in human populations is difficult. To circumvent this our laboratory has chosen to apply a systems genetics approach on a mouse model of metastatic luminal breast cancer, the FVB/N-TgN(MMTV-PyMT)634Mul (MMTV-PyMT) transgenic model. When the MMTV-PyMT model is bred onto a variety of different mouse strains, the F1 progeny display broad and strain-dependent heterogeneity in primary tumor latency, primary tumor growth rate and lung metastatic density [2]
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