C35 overexpression defines subsets of human breast cancer and its immunoreceptor tyrosine-based activation motif represents a novel treatment target

C35 is a protein overexpressed in invasive breast cancer. The C35 gene is located on chromosome 17, next to ERBB2/HER2. C35 encodes a canonical immunoreceptor tyrosine-based activation motif (ITAM) sequence. ITAM-containing proteins have key signalling roles in the hematopoietic system and in oncogenic retroviruses. The ITAM interacts with Syk kinase, which mediates downstream signalling events.

C35-overexpressing breast tumours were found to be of two subsets. In one subset, C35 is coexpressed with HER2. The second subset is found within the basal-like carcinoma group. In order to evaluate the therapeutic potential of targeting C35 ITAM/Syk signalling, we utilised 3D cell cultures. Transformed cell lines act in a manner resembling their in vivo behaviour when grown in 3D cultures, on reconstituted basement membrane. Using this method, C35-expressing cells formed enlarged structures in both an ITAM-dependent and Syk-dependent manner. Furthermore, BT474 cells coexpressing C35 and HER2 formed more normal 3D structures when treated with a combination of Herceptin and Syk inhibitors.