The SUM-229 cell line is one of those aggressive triple negative cell lines characterized by activation of the classical KRAS point mutation in the context of TP53 mutation. Thus, in this cell line, a mutation in KRAS is a driving oncogene. Clearly, in our field we have not been particularly successful at identifying the signaling pathways that are connected to KRAS activation that make the cells as aggressive as they are. As I have examined our shRNA screen data from this cell line, I have been struck by how active the TGF-beta, WNT, and HIPPO pathways are in these cells. Each of these pathways are linked by the common presence of SMAD3, which was a hit in the screen. The TGF-beta pathway shows hits in more than one TGF-beta family ligand, as well as TGFBR2, and downstream components of the signaling system. Similarly, the WNT pathway appears to be particularly important as indicated by screen data. Thus, if it is true that aggressive breast cancer cells are enriched for cells with stem cell characteristics, the activity of these pathways may be clues to the nature of the SUM-229 cells. The extent to which any of this may be related to KRAS mutations is not known.
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