Hsp90 and PKM2 drive the expression of aromatase in Li-Fraumeni syndrome breast adipose stromal cells

Kotha Subbaramaiah, Kristy A. Brown, Heba Zahid, Gabriel Balmus, Robert S. Weiss, Brittney-Shea Herbert, Andrew J. Dannenberg

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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 cochaperone 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.

Original languageEnglish (US)
Pages (from-to)16011-16023
Number of pages13
JournalJournal of Biological Chemistry
Volume291
Issue number31
DOIs
StatePublished - Jul 29 2016

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Li-Fraumeni Syndrome
Aromatase
Stromal Cells
Adenosine Triphosphatases
Breast
Tissue
Germ-Line Mutation
Biosynthesis
p53 Genes
Human Mammary Glands
Ports and harbors
Estrogens
Down-Regulation
Genes

ASJC Scopus subject areas

  • Biochemistry
  • Medicine(all)
  • Molecular Biology
  • Cell Biology

Cite this

Hsp90 and PKM2 drive the expression of aromatase in Li-Fraumeni syndrome breast adipose stromal cells. / Subbaramaiah, Kotha; Brown, Kristy A.; Zahid, Heba; Balmus, Gabriel; Weiss, Robert S.; Herbert, Brittney-Shea; Dannenberg, Andrew J.

In: Journal of Biological Chemistry, Vol. 291, No. 31, 29.07.2016, p. 16011-16023.

Research output: Contribution to journalArticle

Subbaramaiah, Kotha ; Brown, Kristy A. ; Zahid, Heba ; Balmus, Gabriel ; Weiss, Robert S. ; Herbert, Brittney-Shea ; Dannenberg, Andrew J. / Hsp90 and PKM2 drive the expression of aromatase in Li-Fraumeni syndrome breast adipose stromal cells. In: Journal of Biological Chemistry. 2016 ; Vol. 291, No. 31. pp. 16011-16023.
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AB - 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 cochaperone 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.

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