Li-Fraumeni syndrome (LFS) patients harbor germ line mutations in the TP53 gene and are at increased risk of
hormone receptor-positive breast
cancers. Recently, elevated levels of
aromatase, the rate-limiting
enzyme for
estrogen biosynthesis, were found in the breast tissue of LFS patients. Although p53 down-regulates
aromatase expression, the underlying mechanisms are incompletely understood. In the present study, we found that LFS stromal cells expressed higher levels of Hsp90
ATPase activity and
aromatase compared with wild-type stromal cells. Inhibition of Hsp90
ATPase suppressed
aromatase expression. Silencing Aha1 (activator of Hsp90
ATPase 1), a co-chaperone of Hsp90 required for its
ATPase activity, led to both inhibition of Hsp90
ATPase activity and reduced
aromatase expression. In comparison with wild-type stromal cells, increased levels of the Hsp90 client
proteins, HIF-1α, and PKM2 were found in LFS stromal cells. A complex comprised of HIF-1α and PKM2 was recruited to the
aromatase promoter II in LFS stromal cells. Silencing either HIF-1α or PKM2 suppressed
aromatase expression in LFS stromal cells.
CP-31398, a p53 rescue compound, suppressed levels of Aha1, Hsp90
ATPase activity, levels of PKM2 and HIF-1α, and
aromatase expression in LFS stromal cells. Consistent with these in vitro findings, levels of Hsp90
ATPase activity, Aha1, HIF-1α, PKM2, and
aromatase were increased in the mammary glands of p53 null versus wild-type mice. PKM2 and HIF-1α were shown to co-localize in the nucleus of stromal cells of LFS breast tissue. Taken together, our results show that the Aha1-Hsp90-PKM2/HIF-1α axis mediates the induction of
aromatase in LFS.