title: Transcriptional network analysis identifies BACH1 as a master regulator of breast cancer bone metastasis.
abstract: The application of functional genomic analysis of breast cancer metastasis has led to the identification of a growing number of organ-specific metastasis genes, which often function in concert to facilitate different steps of the metastatic cascade. However, the gene regulatory network that controls the expression of these metastasis genes remains largely unknown. Here, we demonstrate a computational approach for the deconvolution of transcriptional networks to discover master regulators of breast cancer bone metastasis. Several known regulators of breast cancer bone metastasis such as Smad4 and HIF1 were identified in our analysis. Experimental validation of the networks revealed BACH1, a basic leucine zipper transcription factor, as the common regulator of several functional metastasis genes, including MMP1 and CXCR4. Ectopic expression of BACH1 enhanced the malignance of breast cancer cells, and conversely, BACH1 knockdown significantly reduced bone metastasis. The expression of BACH1 and its target genes was linked to the higher risk of breast cancer recurrence in patients. This study established BACH1 as the master regulator of breast cancer bone metastasis and provided a paradigm to identify molecular determinants in complex pathological processes.
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai JiaoTong University School of Medicine, Shanghai, China.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Liang
authors.forename: Heng
authors.initials: H
authors.lastname: Wu
authors.forename: Rong
authors.initials: R
authors.lastname: Lei
authors.forename: Robert A
authors.initials: RA
authors.lastname: Chong
authors.forename: Yong
authors.initials: Y
authors.lastname: Wei
authors.forename: Xin
authors.initials: X
authors.lastname: Lu
authors.forename: Ilias
authors.initials: I
authors.lastname: Tagkopoulos
authors.forename: Sun-Yuan
authors.initials: SY
authors.lastname: Kung
authors.forename: Qifeng
authors.initials: Q
authors.lastname: Yang
authors.forename: Guohong
authors.initials: G
authors.lastname: Hu
authors.forename: Yibin
authors.initials: Y
authors.lastname: Kang
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000502:physiology*; D001859:Bone Neoplasms / Q000556:secondary*; D001842:Bone and Bones / Q000473:pathology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D000860:Hypoxia; D015674:Mammary Neoplasms, Animal / Q000378:metabolism; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000473:pathology; D011401:Promoter Regions, Genetic; D051785:Smad Proteins / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C102108:BACH1 protein, human; C486316:Bach1 protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; D051856:Fanconi Anemia Complementation Group Proteins; D051785:Smad Proteins; D020781:Matrix Metalloproteinase 1