What is the Significance of FAS Overexpression in Cancer Cells

Is FAS over-expression a marker only associated with aggressive solid tumours or is it actively engaged in mammary carcinogenesis? FAS activity and endogenous fatty acid synthesis are required for normal embryonic development since FAS gene knock-out is lethal in mice (43). In normal adult cells, except in lactating mammary glands (30), FAS activity is low since fatty acids are mostly provided by food and imported from local vascularization (47).

The use of our specific FAS antibodies on formalin-fixed paraffin embedded sections of mammary tumours have shown that FAS is specifically overexpressed in BC cells and not in adjacent normal ducts lobules or stromal cells (M.Esslimani Sahla, et a,l in preparation).

We hypothesize that in solid tumours the bio-availability of fatty acids from the circulation is weak because their vascularization is generally poor, as also indicated by the lower extra-cellular pH. BC cells overexpressing FAS may have a growth advantage compared to normal peripheral cells in these solid tumours. Cancer cells require nutrients to grow, and not only mitogens. In addition to proteins, they also need fatty acids as precursors for synthesis of membranes, lipid mediators and lipid anchors and they may use FAS for endogenous synthesis of these fatty acids. FAS endogenous activity seems necessary for development of the embryo (48) and for growth of cancer cells, as supported by the specific effects of cerulenine or C75, which block proliferation of breast and ovarian cancer cells and induce apoptosis, while normal cells are insensitive (43, 44, 49, 50). This inhibitory effect is suppressed by adding an excess of palmitic acid, the major product of FAS activity. This clearly indicates that cancer cells require FAS activity for their sustained growth and suggests that FAS could be a potential target in the treatment of hormone-dependant and independent BCs.

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