CD146 and breast cancer migration Free

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CD146 - also known as Mel-CAM, MUC18, A32 antigen and S-endo-1 - is a member of the immunoglobulin gene superfamily, and is involved in heterophilic cell-cell interactions. CD146 is expressed on normal and malignant human tissues.

CD146 expression was shown to be associated with tumor progression and establishment of metastases in several models of human neoplasms, including melanomas, prostate cancers and osteosarcomas. In contrast, CD146 was described as a tumor suppressor gene, in a still-unconfirmed report on breast cancer (Shih et al, 1997).

Our preliminary observations indicates that the level of CD146 expression discriminates two groups of human breast cancer cell lines, with different morphologic, phenotypic, in vitro and in vivo behaviors. In fact most aggressive cell lines display high levels of CD146, in contrast with non-aggressive cell lines that are essentially negative. In addition, DNA micro-arrays demonstrates that primary human basal breast tumors with poor clinical outcome display higher levels of CD146 mRNA than luminal tumors. Together with already published results, that show the expression of CD146 on marrow micro-metastatic cells, as well as the association of CD146 in the primary tumor molecular signature with the frequency of bone marrow metastases, our observations suggest that CD146 may contribute to tumor aggressiveness. We hypothesized that CD146 may do so by promoting tumor cell migration.

Thus, we explored the association between CD146 expression and cell migration in an in vitro assay, using wild-type and genetically modified human breast cancer cell lines. Down modulation of CD146 on MDA-MB-231 and Sum 159PT cell lines using SiRNA technology, resulted in a marked decrease in migration in a Boyden chamber, in response to a chemotactic signal. In an in vitro wound healing assay, the wild-type Sum159PT cells migrated concentrically to cover the wound, while Sum159PT cells transfected with a siRNA targeting CD146 displayed disorganized migration and delayed wound healing.

Human cell lines that express the highest levels of CD146 display features of epithelio-to-mesenchymal transition (EMT). This lead us to hypothesize that CD146 may in addition be a marker of cancer dedifferentiation. Indeed, in the normal human mammary gland, CD146 is expressed on endothelial cells, on myo-epithelial/basal cells, as well as on a minor subset of the luminal epithelium. Exposing MCF-10A, a human CD146 positive breast cell line, to TGF beta results in EMT, which is accompanied by a significant and reproducible increase in CD146 expression (a six fold increase). A similar result can be accomplished with the MuNMG murine cell line.

Altogether, these preliminary results suggest that CD146 may be a marker of human mammary gland differentiation, and may be associated with a more aggressive phenotype of human breast cancers, through promotion of tumor aggressiveness and invasion. Further experiments are needed to confirm these hypotheses.