Role of Teneurin 4 in Triple Negative Breast Cancer progression

Triple-negative breast cancer (TNBC) is recognized as one of the most aggressive forms of breast cancer among women worldwide. The unfavourable prognosis for TNBC patients is primarily attributed to the absence of targetable molecules and the limited effectiveness of current therapies in eradicating Cancer Stem Cells (CSC). In response to these challenges, the focal point of investigation revolves around identifying innovative targets for TNBC stem cells, holding the promise of developing novel therapeutic strategies. Recently, Teneurin 4 (TENM4) has emerged as highly overexpressed in the CSC of TNBC. Thus, this thesis aims to evaluate the role of TENM4 in TNBC by exploiting the murine TNBC cell line 4T1, in which TENM4 is silenced using Short Hairpin technology. Results revealed a significant impairment in cell proliferation and migration in TENM4-deficient compared to TENM4-expressing cells. Notably, the silencing of TENM4 led to decreased of the focal adhesion kinase (FAK) phosphorylation, suggesting that TENM4 may act on cell migration through FAK pathway. Furthermore, the absence of TENM4 resulted in the impairment of 4T1 tumorsphere forming ability, accompanied by a reduction in tumorsphere derived as compared to epithelial cells of stemness markers expression such as the octamer-binding transcription factor 4 (OCT4). Moreover, while no significant difference in tumor growth was observed in mice injected with 4T1-deficient cells compared to TENM4-expressing cells, a reduction in the number of lung metastases was revealed, underscoring, for the first time in vivo, the involvement of TENM4 in cancer stemness, invasion and TNBC progression. A deeper understanding of TENM4 in this pathology may pave the way for novel therapeutic strategies, mitigating the aggressive behaviour of TNBC and enhancing patients’ clinical outcome.