Netrin-1: a promising therapeutic target in metastatic breast cancer. Expression analysis in localized and metastatic breast tumors and preclinical validation.
Authors: J Fitamant, C Guenebeaud, I Treilleux, E Tabone, S Chabot, A Bernet, P Mehlen, T Bachelot
Journal: Cancer Research (2009)

Abstract Abstract #3075 Netrin-1, an axon navigation cue was proposed to play a crucial role during colorectal tumorigenesis by regulating apoptosis. The netrin-1 receptors DCC and UNC5H belong to the family of dependence receptors that share the ability to induce apoptosis in the absence of their ligand. Cells expressing one of these dependence receptors are thus dependent on ligand availability to survive. Such a trait confers on these receptors a tumor suppressor activity by preventing uncontrolled cell proliferation.&amp;#x2028; We have previously shown in breast cancer that gaining autocrine expression of the ligand netrin-1 would represent for cancer cells a selective advantage. Human and murine netrin-1-expressing mammary metastatic cell lines undergo apoptosis when netrin-1 expression is experimentally decreased or when decoy soluble receptor ectodomains are used. Such treatments prevent metastasis formation in a syngenic mouse model of lung colonization by a mammary cancer cell line (Fitamant et al., PNAS 2008, vol 105).&amp;#x2028; In order to assess the clinical importance of netrin-1 expression in human breast cancer, we quantified by Q-RT-PCR the mRNA levels of netrin-1 in primary breast cancer biopsies and studied their correlation to pathological and clinical data. We used frozen tumor samples from 120 breast cancer patients treated in our institution between 1993 and 2000. At diagnosis, median age was 50, median tumor size was 40 mm. 11% of the patients had SBR1 tumor, 46% had SBR2 tumor and 43% had SBR3 tumor. Estrogen receptor was positive for 62% of the patients. 17% of the patients were pN0, M0; 71% were pN+, M0 and 12% already had distant metastasis (M+) at time of diagnosis. Although there is no correlation between netrin-1 expression and tumor size, histological SBR grade or hormone receptor status, there is a strong correlation between high netrin-1 expression and the presence of nodal involvement (p=0,007) or distant metastasis at the time of diagnosis (p&amp;lt;0,0001). We hypothesize that high netrin-1 expression allows an early and rapid metastatic dissemination during tumor development. We are currently exploring netrin-1 expression levels at different metastatic sites and are completing survival analysis of our cohort of patients.&amp;#x2028; In parallel, preclinical mice models of xenografts either of human breast cancer cell lines or fresh human breast tumors were used to evaluate netrin-1 targeting strategy. The preliminary results show that disrupting netrin-1 activity appears to be more efficient than a conventional Adryamicin-Cyclophosphamide treatment in decreasing tumor sizes and suppressing lung metastasis.&amp;#x2028; These results support netrin-1 as a marker of metastatic dissemination and as a promising therapeutic target in breast cancer progression. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3075.