title: Hsp90 and PKM2 Drive the Expression of Aromatase in Li-Fraumeni Syndrome Breast Adipose Stromal Cells.
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 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.
authors.affiliation: From the Department of Medicine, Weill Cornell Medical College, New York, New York 10065, ksubba@med.cornell.edu.
authors.forename: Kotha
authors.initials: K
authors.lastname: Subbaramaiah
authors.affiliation: the Metabolism and Cancer Laboratory, Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Kristy A
authors.initials: KA
authors.lastname: Brown
authors.affiliation: the Metabolism and Cancer Laboratory, Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia, Monash University, Clayton, Victoria 3800, Australia, the Faculty of Applied Medical Science, Taibah University, Medina, Saudi Arabia.
authors.forename: Heba
authors.initials: H
authors.lastname: Zahid
authors.affiliation: the Department of Biomedical Sciences, Cornell University, Ithaca, New York 14853, and.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Balmus
authors.affiliation: the Department of Biomedical Sciences, Cornell University, Ithaca, New York 14853, and.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Weiss
authors.affiliation: the Department of Medical and Molecular Genetics, Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: Brittney-Shea
authors.initials: BS
authors.lastname: Herbert
authors.affiliation: From the Department of Medicine, Weill Cornell Medical College, New York, New York 10065.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Dannenberg
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001141:Aromatase / Q000096:biosynthesis* / Q000235:genetics; D001940:Breast / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008321:Mammary Glands, Animal / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D013963:Thyroid Hormones / Q000235:genetics / Q000378:metabolism*; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D001141:Aromatase; D002352:Carrier Proteins; D018841:HSP90 Heat-Shock Proteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins; C515652:AHSA1 protein, human; C575823:Ahsa1 protein, mouse; C561410:CYP19A1 protein, human
keywords: heat shock protein 90 (Hsp90); hypoxia-inducible factor (HIF); p53; pyruvate kinase; signal transduction