Inhibition of the 11q13 amplified calcium activated chloride channel ANO1 reduces Head and Neck and Breast cancer growth

The 11q13 amplicon is one of the most frequently amplified chromosomal regions in human cancer and correlates with poor prognosis1-3. CCDN1, EMS1 and FGF19 have been considered as the main tumor promoting genes contained in this amplicon4,5. Recently, another gene located in the 11q13 amplicon, anoctamin 1 (ANO1, also known as TMEM16A, DOG-1, ORAOV2, TAOS2) was found to be highly expressed in squamous carcinoma of the head & neck (HNSCC), of the esophagus (ESCC), and in GIST6-8. ANO1 has also been shown to be required for head and neck tumor cell growth9. However, the precise role of ANO1, a calcium-activated chloride channel, in tumorigenesis is unknown10-12. Here we introduce ANO1 as a new driver of oncogenesis in HNSCC, ESCC and breast cancer. We found ANO1 to be highly expressed in ~90% of HNSCC, ESCC and ~70% of breast tumors analyzed. Knockdown of ANO1 in HNSCC, ESCC and breast cancer cell lines inhibits proliferation in vitro and in vivo and induces apoptosis by decreasing EGFR-, CAMKII- signaling and subsequently Akt-and ERK-activation. Our results establish an example of the long-sought role of chloride channels in tumorigenesis and provide new insight for oncogenic signaling and therapeutic intervention in HNSCC, ESCC and breast cancer