Calcium-activated chloride channel ANO1 promotes breast cancer progression by activating EGFR and CAMK signaling

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.ion channel | CaCCinh-A01 | TMEM16A | HNSCC | ESCC

Role of volume-regulated and calcium-activated anion channels in cell volume homeostasis, cancer and drug resistance

“…A pro-proliferative role of ANO1 is found in most cancer cells investigated 118,[141][142][143][144][145][146] and Stanich and coworkers demonstrated that ANO1 regulates cell proliferation at the G1/S transition in the cell cycle. 147 Other studies, however, show that cell proliferation in certain cell types is unaffected by ANO1, e.g.…”

Variomics Screen Identifies the Re-entrant Loop of the Calcium-activated Chloride Channel ANO1 That Facilitates Channel Activation

“…The physiological relevance of ANO1 is further underscored by several disease states associated with ANO1 dysfunction, including asthma, gastroparesis, hypertension, rota-virus-induced diarrhea, polycystic kidney disease, as well as its high expression and amplification in various cancers (12)(13)(14)(15)(16)(17).…”

Identification and characterization of a novel promoter for the human ANO1 gene regulated by the transcription factor signal transducer and activator of transcription 6 (STAT6)

“…Aberrant expression and activity of Ano1 have also been implicated in the pathophysiology of several diseases, including cancer (20)(21)(22)(23), cystic fibrosis (24), and hypertension (25)(26)(27). It has been identified as a possible therapeutic target in cystic fibrosis and asthma (24,28), as well as hypertension-associated cardiovascular diseases such as stroke (25,26) and pulmonary hypertension (27).…”

“…For example, in the lung, IL-4 is a potent inducer of Ano1 expression (1) and may be important in the pathophysiology of asthma (29). In several cancers, Ano1 expression is also highly up-regulated by mechanisms that are not fully established (20)(21)(22)(23).…”