dc.contributor.author | Xiao, T | |
dc.contributor.author | Li, W | |
dc.contributor.author | Wang, X | |
dc.contributor.author | Xu, H | |
dc.contributor.author | Yang, J | |
dc.contributor.author | Wu, Q | |
dc.contributor.author | Huang, Y | |
dc.contributor.author | Geradts, J | |
dc.contributor.author | Jiang, P | |
dc.contributor.author | Fei, T | |
dc.contributor.author | Chi, D | |
dc.contributor.author | Zang, C | |
dc.contributor.author | Liao, Q | |
dc.contributor.author | Rennhack, J | |
dc.contributor.author | Andrechek, E | |
dc.contributor.author | Li, N | |
dc.contributor.author | Detre, S | |
dc.contributor.author | Dowsett, M | |
dc.contributor.author | Jeselsohn, RM | |
dc.contributor.author | Liu, XS | |
dc.contributor.author | Brown, M | |
dc.date.accessioned | 2018-07-31T11:50:53Z | |
dc.date.issued | 2018-07-09 | |
dc.identifier.citation | Proceedings of the National Academy of Sciences of the United States of America, 2018, 115 (31), pp. 7869 - 7878 | |
dc.identifier.issn | 0027-8424 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/2230 | |
dc.identifier.eissn | 1091-6490 | |
dc.identifier.doi | 10.1073/pnas.1722617115 | |
dc.description.abstract | Endocrine therapy resistance invariably develops in advanced estrogen receptor-positive (ER+) breast cancer, but the underlying mechanisms are largely unknown. We have identified C-terminal SRC kinase (CSK) as a critical node in a previously unappreciated negative feedback loop that limits the efficacy of current ER-targeted therapies. Estrogen directly drives CSK expression in ER+ breast cancer. At low CSK levels, as is the case in patients with ER+ breast cancer resistant to endocrine therapy and with the poorest outcomes, the p21 protein-activated kinase 2 (PAK2) becomes activated and drives estrogen-independent growth. PAK2 overexpression is also associated with endocrine therapy resistance and worse clinical outcome, and the combination of a PAK2 inhibitor with an ER antagonist synergistically suppressed breast tumor growth. Clinical approaches to endocrine therapy-resistant breast cancer must overcome the loss of this estrogen-induced negative feedback loop that normally constrains the growth of ER+ tumors. | |
dc.format | Print-Electronic | |
dc.format.extent | 7869 - 7878 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Humans | |
dc.subject | Breast Neoplasms | |
dc.subject | src-Family Kinases | |
dc.subject | Neoplasm Proteins | |
dc.subject | Receptors, Estrogen | |
dc.subject | Estrogens | |
dc.subject | Gene Expression Regulation, Enzymologic | |
dc.subject | Gene Expression Regulation, Neoplastic | |
dc.subject | Female | |
dc.subject | p21-Activated Kinases | |
dc.subject | MCF-7 Cells | |
dc.title | Estrogen-regulated feedback loop limits the efficacy of estrogen receptor-targeted breast cancer therapy. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2018-06-15 | |
rioxxterms.versionofrecord | 10.1073/pnas.1722617115 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by-nc-nd/4.0 | |
rioxxterms.licenseref.startdate | 2018-07-09 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Proceedings of the National Academy of Sciences of the United States of America | |
pubs.issue | 31 | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Endocrinology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology/Endocrinology (hon.) | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Endocrinology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology/Endocrinology (hon.) | |
pubs.publication-status | Published | |
pubs.volume | 115 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Endocrinology | en_US |
dc.contributor.icrauthor | Dowsett, Mitch | en |