CD146 or Mel-CAM, a member of the immunoglobulin-like CAM family, is activated through a dimerization of its ligand, leading to a cascade of signal transduction events. While CD146 is a promoter of melanoma and prostate cancer, its role in BC remains nascent and controversial. However, we have recently reported that CD146, a negative transcriptional target of CD44-HA downstream signaling, suppresses breast tumor cell invasion; this has prompted us to generate the hypothesis that CD146 acts as a tumor suppressor in BC via its downstream transcriptional targets.
To test this hypothesis, we developed both in vitro and in vivo tetracycline (tet On)-inducible system of CD146 using MDA-MB-231 founder BC cell line. Our results demonstrated that induction of CD146 suppressed BC cell migration and invasion in vitro as well as tumor growth and progression in mouse breast xenograft model. Microarray gene expression profiling revealed latexin (LXN: a variant of Tissue Inhibitor of Metalloproteinases) as a novel potential CD146-downstream signaling transcriptional target, which was validated using various in vitro approaches.
To further validate our finding in vivo, immunohistochemical analysis of breast tumor tissues from both human and mouse (tet-inducible system) breast tissues showed that, while the expression of both CD146 and LXN were highly expressed in the early stages of BC (normal and benign tissues), it was lost in advanced stages (malignant and metastatic tissues). Pharmacological approach combined with luciferase assay revealed that NFκB activation via Akt pathway couples CD146 to the transcription of LXN in BC CD146inducible cells.
The present study discovers the main molecular players of a novel signaling pathway, CD146/LXN/Akt/N-κB, by which CD146 acts as a suppressor of BC progression.
Allal Ouhtit.
Qatar University.
All authors have declared no conflicts of interest.