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dc.contributor.authorWhitesell, Luke
dc.contributor.authorSantagata, Sandro
dc.contributor.authorMendillo, Marc L.
dc.contributor.authorLin, Nancy U.
dc.contributor.authorProia, David A.
dc.contributor.authorLindquist, Susan
dc.date.accessioned2015-06-30T17:11:34Z
dc.date.available2015-06-30T17:11:34Z
dc.date.issued2014-12
dc.date.submitted2014-08
dc.identifier.issn0027-8424
dc.identifier.issn1091-6490
dc.identifier.urihttp://hdl.handle.net/1721.1/97588
dc.description.abstractThe efficacy of hormonal therapies for advanced estrogen receptor-positive breast cancers is limited by the nearly inevitable development of acquired resistance. Efforts to block the emergence of resistance have met with limited success, largely because the mechanisms underlying it are so varied and complex. Here, we investigate a new strategy aimed at the very processes by which cancers evolve resistance. From yeast to vertebrates, heat shock protein 90 (HSP90) plays a unique role among molecular chaperones by promoting the evolution of heritable new traits. It does so by regulating the folding of a diverse portfolio of metastable client proteins, many of which mediate adaptive responses that allow organisms to adapt and thrive in the face of diverse challenges, including those posed by drugs. Guided by our previous work in pathogenic fungi, in which very modest HSP90 inhibition impairs resistance to mechanistically diverse antifungals, we examined the effect of similarly modest HSP90 inhibition on the emergence of resistance to antiestrogens in breast cancer models. Even though this degree of inhibition fell below the threshold for proteotoxic activation of the heat-shock response and had no overt anticancer activity on its own, it dramatically impaired the emergence of resistance to hormone antagonists both in cell culture and in mice. Our findings strongly support the clinical testing of combined hormone antagonist-low-level HSP90 inhibitor regimens in the treatment of metastatic estrogen receptor-positive breast cancer. At a broader level, they also provide promising proof of principle for a generalizable strategy to combat the pervasive problem of rapidly emerging resistance to molecularly targeted therapeutics.en_US
dc.language.isoen_US
dc.publisherNational Academy of Sciences (U.S.)en_US
dc.relation.isversionofhttp://dx.doi.org/10.1073/pnas.1421323111en_US
dc.rightsArticle is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.en_US
dc.sourceNational Academy of Sciences (U.S.)en_US
dc.titleHSP90 empowers evolution of resistance to hormonal therapy in human breast cancer modelsen_US
dc.typeArticleen_US
dc.identifier.citationWhitesell, Luke, Sandro Santagata, Marc L. Mendillo, Nancy U. Lin, David A. Proia, and Susan Lindquist. “HSP90 Empowers Evolution of Resistance to Hormonal Therapy in Human Breast Cancer Models.” Proceedings of the National Academy of Sciences 111, no. 51 (December 8, 2014): 18297–18302.en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.contributor.departmentWhitehead Institute for Biomedical Researchen_US
dc.contributor.mitauthorLindquist, Susanen_US
dc.relation.journalProceedings of the National Academy of Sciencesen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsWhitesell, Luke; Santagata, Sandro; Mendillo, Marc L.; Lin, Nancy U.; Proia, David A.; Lindquist, Susanen_US
dc.identifier.orcidhttps://orcid.org/0000-0003-1307-882X
mit.licensePUBLISHER_POLICYen_US


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