RRC ID 69813
Author Britschgi A, Bill A, Brinkhaus H, Rothwell C, Clay I, Duss S, Rebhan M, Raman P, Guy CT, Wetzel K, George E, Popa MO, Lilley S, Choudhury H, Gosling M, Wang L, Fitzgerald S, Borawski J, Baffoe J, Labow M, Gaither LA, Bentires-Alj M.
Title Calcium-activated chloride channel ANO1 promotes breast cancer progression by activating EGFR and CAMK signaling.
Journal Proc Natl Acad Sci U S A
Abstract The calcium-activated chloride channel anoctamin 1 (ANO1) is located within the 11q13 amplicon, one of the most frequently amplified chromosomal regions in human cancer, but its functional role in tumorigenesis has remained unclear. The 11q13 region is amplified in ∼15% of breast cancers. Whether ANO1 is amplified in breast tumors, the extent to which gene amplification contributes to ANO1 overexpression, and whether overexpression of ANO1 is important for tumor maintenance have remained unknown. We have found that ANO1 is amplified and highly expressed in breast cancer cell lines and primary tumors. Amplification of ANO1 correlated with disease grade and poor prognosis. Knockdown of ANO1 in ANO1-amplified breast cancer cell lines and other cancers bearing 11q13 amplification inhibited proliferation, induced apoptosis, and reduced tumor growth in established cancer xenografts. Moreover, ANO1 chloride channel activity was important for cell viability. Mechanistically, ANO1 knockdown or pharmacological inhibition of its chloride-channel activity reduced EGF receptor (EGFR) and calmodulin-dependent protein kinase II (CAMKII) signaling, which subsequently attenuated AKT, v-src sarcoma viral oncogene homolog (SRC), and extracellular signal-regulated kinase (ERK) activation in vitro and in vivo. Our results highlight the involvement of the ANO1 chloride channel in tumor progression and provide insights into oncogenic signaling in human cancers with 11q13 amplification, thereby establishing ANO1 as a promising target for therapy in these highly prevalent tumor types.
Volume 110(11)
Pages E1026-34
Published 2013-3-12
DOI 10.1073/pnas.1217072110
PII 1217072110
PMID 23431153
PMC PMC3600458
MeSH Animals Anoctamin-1 Apoptosis / genetics Breast Neoplasms / genetics Breast Neoplasms / metabolism* Breast Neoplasms / pathology Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism* Cell Line, Tumor Cell Survival / genetics Chloride Channels / genetics Chloride Channels / metabolism* Chromosomes, Human, Pair 11 / genetics Chromosomes, Human, Pair 11 / metabolism* Enzyme Activation / genetics ErbB Receptors / genetics ErbB Receptors / metabolism Female Gene Amplification* Gene Knockdown Techniques Humans Mice Mice, Inbred NOD Mice, SCID Neoplasm Proteins / genetics Neoplasm Proteins / metabolism* Neoplasm Transplantation Signal Transduction / genetics Transplantation, Heterologous
IF 9.412
Human and Animal Cells TE-1(RCB1894) TE-9(RCB1988) TE-11(RCB2100)