ER+ Breast Cancers Resistant to Prolonged Neoadjuvant Letrozole Exhibit an E2F4 Transcriptional Program Sensitive to CDK4/6 Inhibitors
DC Field | Value | Language |
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dc.contributor.author | Guerrero-Zotano, Angel L | - |
dc.contributor.author | Stricker, Thomas P | - |
dc.contributor.author | Formisano, Luigi | - |
dc.contributor.author | Hutchinson, Katherine E | - |
dc.contributor.author | Stover, Daniel G | - |
dc.contributor.author | Lee, Kyung min | - |
dc.contributor.author | Schwarz, Luis J | - |
dc.contributor.author | Giltnane, Jennifer M | - |
dc.contributor.author | Estrada, Monica V | - |
dc.contributor.author | Jansen, Valerie M | - |
dc.date.accessioned | 2022-07-07T02:39:57Z | - |
dc.date.available | 2022-07-07T02:39:57Z | - |
dc.date.created | 2021-05-14 | - |
dc.date.issued | 2018-06 | - |
dc.identifier.issn | 1078-0432 | - |
dc.identifier.uri | https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/142623 | - |
dc.description.abstract | Purpose: This study aimed to identify biomarkers of resistance to endocrine therapy in estrogen receptor–positive (ER+) breast cancers treated with prolonged neoadjuvant letrozole. Experimental Design: We performed targeted DNA and RNA sequencing in 68 ER+ breast cancers from patients treated with preoperative letrozole (median, 7 months). Results: Twenty-four tumors (35%) exhibited a PEPI score ≥4 and/or recurred after a median of 58 months and were considered endocrine resistant. Integration of the 47 most upregulated genes (log FC > 1, FDR < 0.03) in letrozole-resistant tumors with transcription-binding data showed significant overlap with 20 E2F4-regulated genes (P = 2.56E−15). In patients treated with the CDK4/6 inhibitor palbociclib before surgery, treatment significantly decreased expression of 24 of the 47 most upregulated genes in letrozole-resistant tumors, including 18 of the 20 E2F4 target genes. In long-term estrogen-deprived ER+ breast cancer cells, palbociclib also downregulated all 20 E2F4 target genes and P-RB levels, whereas the ER downregulator fulvestrant or paclitaxel only partially suppressed expression of this set of genes and had no effect on P-RB. Finally, an E2F4 activation signature was strongly associated with resistance to aromatase inhibitors in the ACOSOG Z1031B neoadjuvant trial and with an increased risk of relapse in adjuvant-treated ER+ tumors in METABRIC. Conclusions: In tumors resistant to prolonged neoadjuvant letrozole, we identified a gene expression signature of E2F4 target activation. CDK4/6 inhibition suppressed E2F4 target gene expression in estrogen-deprived ER+ breast cancer cells and in patients’ ER+ tumors, suggesting a potential benefit of adjuvant CDK4/6 inhibitors in patients with ER+ breast cancer who fail to respond to preoperative estrogen deprivation. Clin Cancer Res; 24(11); 1–13. ©2018 AACR. | - |
dc.language | 영어 | - |
dc.language.iso | en | - |
dc.publisher | AMER ASSOC CANCER RESEARCH | - |
dc.title | ER+ Breast Cancers Resistant to Prolonged Neoadjuvant Letrozole Exhibit an E2F4 Transcriptional Program Sensitive to CDK4/6 Inhibitors | - |
dc.title.alternative | ERþ Breast cancers resistant to prolonged neoadjuvant letrozole exhibit an e2f4 transcriptional program sensitive to cdk4/6 inhibitors | - |
dc.type | Article | - |
dc.contributor.affiliatedAuthor | Lee, Kyung min | - |
dc.identifier.doi | 10.1158/1078-0432.CCR-17-2904 | - |
dc.identifier.scopusid | 2-s2.0-85048092034 | - |
dc.identifier.wosid | 000433971400008 | - |
dc.identifier.bibliographicCitation | CLINICAL CANCER RESEARCH, v.24, no.11, pp.2517 - 2529 | - |
dc.relation.isPartOf | CLINICAL CANCER RESEARCH | - |
dc.citation.title | CLINICAL CANCER RESEARCH | - |
dc.citation.volume | 24 | - |
dc.citation.number | 11 | - |
dc.citation.startPage | 2517 | - |
dc.citation.endPage | 2529 | - |
dc.type.rims | ART | - |
dc.type.docType | 정기학술지(Article(Perspective Article포함)) | - |
dc.description.journalClass | 1 | - |
dc.description.isOpenAccess | Y | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
dc.relation.journalResearchArea | Oncology | - |
dc.relation.journalWebOfScienceCategory | Oncology | - |
dc.subject.keywordPlus | ENDOCRINE THERAPY | - |
dc.subject.keywordPlus | TAMOXIFEN | - |
dc.subject.keywordPlus | PROLIFERATION | - |
dc.subject.keywordPlus | ANASTROZOLE | - |
dc.subject.keywordPlus | CHEMOTHERAPY | - |
dc.subject.keywordPlus | ARCHITECTURE | - |
dc.subject.keywordPlus | VALIDATION | - |
dc.subject.keywordPlus | PREDICTION | - |
dc.subject.keywordPlus | SERVER | - |
dc.subject.keywordPlus | TRIAL | - |
dc.identifier.url | https://aacrjournals.org/clincancerres/article/24/11/2517/80819/ER-Breast-Cancers-Resistant-to-Prolonged | - |
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