Anti-SPTAN1 monoclonal antibody, clone 4E8

SH3 domain-binding glutamic acid-rich-like protein 2 (SH3BGRL2) is a poorly defined member of the SH3BGR gene family with potential roles in cell differentiation and tissue development. Here, we report for the first time that SH3BGRL2 exerts a dual function in breast tumor growth and metastasis. SH3BGRL2 was downregulated in a subset of primary breast tumors, and suppressed breast cancer cell proliferation and colony formation in vitro and xenograft tumor growth in vivo. Strikingly, SH3BGRL2 enhanced breast cancer cell migratory, invasive, and lung metastatic capacity. Mechanistic investigations revealed that SH3BGRL2 interacted with and transcriptionally repressed spectrin alpha, non-erythrocytic 1 (SPTAN1) and spectrin beta, non-erythrocytic 1 (SPTBN1), two important cytoskeletal proteins. Functional rescue assays further demonstrated that depletion of SH3BGRL2 reduced breast cancer cell invasive potential, which was partially rescued by knockdown of SPTAN1 and SPTBN1 using specific small interfering RNA. Moreover, transforming growth factor-beta 1 (TGF-beta 1) transcriptionally activated SH3BGRL2 expression in breast cancer cells through the canonical TGF-beta receptor-Smad pathway. Collectively, these results establish a dual function of SH3BGRL2 in breast cancer growth and metastasis and uncover SH3BGRL2 as a downstream target of the TGF-beta 1 signaling pathway in breast cancer cells.

BACKGROUND: Microdeletion of chromosome 9q33q34 is an emerging disease disorder associated with early infantile epileptic encephalopathy, intellectual disability, and a variety of movement disorders. PATIENT: We describe a male infant with early infantile epileptic encephalopathy with suppression-burst (Ohtahara syndrome) who carried a de nova 2.0-Mb microdeletion in chromosome 9q33q34, including STXBP1. The previously reported examples of 9q33q34 microdeletion including STXBP1 are reviewed. RESULTS: The patient developed infantile spasms at 4 months of age, and these were refractory to multiple antiepileptic drugs. He also developed severe dystonia during infancy, rotatory nystagmus, and nephroureteral malformations. Immunoglobulin and clobazam administered at 11 months were effective for the spasms, but profound psychomotor retardation remained. A comparative genomic hybridization array analysis and the fluorescence in situ hybridization analysis revealed a de nova 2.0-Mb microdeletion in chromosome 9q33q34, which encompasses STXBP1, ENG, SPTAN1, and 52 other genes. A total of 14 patients (13 from the literature) with a 9q33q24 microdeletion including STXBP1 were reviewed, five of them displayed early infantile epileptic encephalopathy with suppression-burst, and six of them had early-onset epilepsy but not early infantile epileptic encephalopathy. Dystonia has been previously described in 9q33q34 deletions involving TOR1A but not STXBP1. Neither abnormal eye movements nor nephroureteral malformations has been previously described. CONCLUSIONS: This patient adds unique clinical presentations of neurological and nephroureteral abnormalities to the features of 9q33q34 microdeletion.