To develop new
therapies for
inflammatory breast cancer (IBC) we have compared the effects of two
hydroxamic acid-based
histone deacetylase (
HDAC) inhibitors,
CG-1521 and
Trichostatin A (
TSA) on the biology of two IBC cell lines: SUM149PT and SUM190PT.
CG-1521 and
TSA induce dose (0-10 µM) and time-dependent (0-96 h) increases in the proportion of cells undergoing cell cycle arrest and apoptosis in the presence or absence of 17β-estradiol. In SUM 149PT cells, both
CG-1521 and
TSA increase the levels of acetylated α-
tubulin; however the morphological effects are different:
CG-1521 blocks mitotic spindle formation and prevents abscission during cytokinesis while
TSA results in an increase in cell size. In SUM190PT cells
CG-1521 does not cause an increase in acetylated-α-
tubulin and even though
TSA significantly increases the levels of acetylated
tubulin, neither inhibitor alters the morphology of the cells. Microarray analysis demonstrates that
CG-1521 modulates the expression of 876 mRNAs and 63
miRNAs in SUM149PT cells, and 1227 mRNAs and 35
miRNAs in SUM190PT cells. Only 9% of the genes are commonly modulated in both cell lines, suggesting that
CG-1521 and
TSA target different biological processes in the two cell lines most likely though the inhibition of different HDACs in these cell lines. Gene ontology (GO) analysis reveals that
CG-1521 affects the expression of mRNAs that encode
proteins associated with the spindle assembly checkpoint, chromosome segregation, and microtubule-based processes in both cell lines and has cell-type specific effects on
lipid biosynthesis, response to DNA damage, and cell death.