title: CREB3L1 is a metastasis suppressor that represses expression of genes regulating metastasis, invasion, and angiogenesis.
abstract: The unfolded protein response (UPR) is activated in response to hypoxia-induced stress such as in the tumor microenvironment. This study examined the role of CREB3L1 (cyclic AMP [cAMP]-responsive element-binding protein 3-like protein 1), a member of the UPR, in breast cancer development and metastasis. Initial experiments identified the loss of CREB3L1 expression in metastatic breast cancer cell lines compared to low-metastasis or nonmetastatic cell lines. When metastatic cells were transfected with CREB3L1, they demonstrated reduced invasion and migration in vitro, as well as a significantly decreased ability to survive under nonadherent or hypoxic conditions. Interestingly, in an in vivo rat mammary tumor model, not only did CREB3L1-expressing cells fail to form metastases compared to CREB3L1 null cells but regression of the primary tumors was seen in 70% of the animals as a result of impaired angiogenesis. Microarray and chromatin immunoprecipitation with microarray technology (ChIP on Chip) analyses identified changes in the expression of many genes involved in cancer development and metastasis, including a decrease in those involved in angiogenesis. These data suggest that CREB3L1 plays an important role in suppressing tumorigenesis and that loss of expression is required for the development of a metastatic phenotype.
authors.affiliation: Saskatchewan Cancer Agency, Cancer Research, Saskatoon, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Mellor
authors.forename: Leah
authors.initials: L
authors.lastname: Deibert
authors.forename: Brian
authors.initials: B
authors.lastname: Calvert
authors.forename: Keith
authors.initials: K
authors.lastname: Bonham
authors.forename: Svein A
authors.initials: SA
authors.lastname: Carlsen
authors.forename: Deborah H
authors.initials: DH
authors.lastname: Anderson
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008207:Lymphatic Metastasis; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D051381:Rats; D011916:Rats, Inbred F344; D059467:Transcriptome; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: C485618:CREB3L1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D025521:Tumor Suppressor Proteins