The neuronal cell adhesion molecule L1CAM as a therapeutic targe in breast cancer.

Abstract

e21138 Background: Brain metastases of breast cancer occurs in approximately one-third of metastatic triple negative and HER2+ breast cancer patients and contributes to patient morbidity and mortality. The identification and validation of molecular pathways underlying brain metastases of breast cancer may lead to the development of effective therapeutics. Methods: We have identified 23 sets of matched primary breast tumors and resected brain metastases, and determined their gene expression profiles using the DASL platform on formalin-fixed, paraffin embedded tumor sections. Multiple independent shRNAs to L1CAM or a control shRNA were transfected into a brain metastatic derivative (231-BR) of human MDA-MB-231 breast carcinoma cells. Brain metastases were quantified one month after intracardiac injection. Results: Patient characteristics: mean age at diagnosis of brain metastases: 48 years (range 29-68 years); 10 HER2+(3+)/ER- (43.5%), 1 HER2(2+)/ER- (4.4%), 2 HER2(2+)/ER+ (8.7%), 3 HER2-/ER+ (13%), 2 HER2(3+)/ER+ (8.7%) 5 triple negative (22%), median time from diagnosis to brain metastases was 2.5 years (range 0 to 11.8 years). Of 502 genes, 12 were significantly overexpressed in brain metastases as compared to matched primary tumors by >1.5 fold; each of the 12 genes was also overexpressed in resected brain metastases as compared to systemic human metastases in an online microarray database. One of these, L1CAM, a neuronal cell adhesion molecule involved in axon motility and tracking, was upregulated 1.6-fold in the brain metastases relative to the primary tumors (p= 0.037). L1CAM protein was upregulated 6.4-fold in 231-BR cells relative to MDA-MB-231. Control shRNA- and L1CAM shRNA transfected 231-BR cells produced equivalent numbers of brain micrometastases; knockdown of L1CAM inhibited the development of large (>1 mm) metastases in a mouse brain by 2-fold (p= 0.038). Conclusions: L1CAM neuronal cell adhesion protein is acquired in human brain metastases of breast cancer and functionally promotes the formation of large brain metastases, identifying it as a new therapeutic target.