Abstract
1953
The identification of different subtypes of breast cancer, based on their molecular features has brought new perspectives in breast cancer.
Moreover, as recently reported, distinct spectra of genomic DNA copy number alterations (CNAs) underlie the different subtypes of breast cancer defined by expression-profiling, implying these subtypes develop along distinct genetic pathways. The basal-like subtype has been shown to have higher overall numbers of DNA gains/losses, the highest proliferation rates and poor clinical outcomes. However, little is known with regard to the development and prevention of these aggressive tumors.
In this study, we identify specific gain at 10p13 related to the basal-like subtype, where a focal recurrent gain harbors CAMK1D, encoding a member of the calcium/calmodulin-dependent protein kinase family with diverse roles. To examine a potential role of CAMK1D amplification/overexpression in breast tumor progression, we overexpressed CAMK1D in immortalized non tumorigenic MCF10A mammary epithelial cells.
MCF10A cells overexpressing CAMK1D exhibited increased cell proliferation, increased invasion in Boyden Chamber assays, and resulted in the acquisition of both morphologic and molecular attributes typical of mesenchymal cells, including expression of vimentin with loss of E-cadherin.
Recent studies have shown that the Ca2+ response elements of c-fos genes are indistinguishable from their CREB-response elements (CREs). We observed that MCF10A cells overexpressing CAMK1D exhibited increased levels of phosphorylation of CREB at Ser133 suggesting a role of transcriptional activation of genes harboring CREs in promoting cell proliferation and invasion.
In conclusion, our data implicate CAMK1D as a key gene within the 10p13 amplicon in human breast cancer, and propose a role for CAMK1D overexpression in driving epithelial-mesenchymal transition during breast cancer progression.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA
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