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Article: AKTIP loss is enriched in ERα-positive breast cancer for tumorigenesis and confers endocrine resistance

TitleAKTIP loss is enriched in ERα-positive breast cancer for tumorigenesis and confers endocrine resistance
Authors
KeywordsCP: Cancer
endocrine resistance
estrogen receptor
luminal breast cancer
protein degradation
Issue Date13-Dec-2022
PublisherCell Press
Citation
Cell Reports, 2022, v. 41, n. 11 How to Cite?
AbstractRecurrent deletion of 16q12.2 is observed in luminal breast cancer, yet the causal genomic alterations in this region are largely unknown. In this study, we identify that loss of AKTIP, which is located on 16q12.2, drives tumorigenesis of estrogen receptor alpha (ERα)-positive, but not ERα-negative, breast cancer cells and is associated with poor prognosis of patients with ERα-positive breast cancer. Intriguingly, AKTIP-depleted tumors have increased ERα protein level and activity. Cullin-associated and neddylation-dissociated protein 1 (CAND1), which regulates the cullin-RING E3 ubiquitin ligases, protects ERα from cullin 2-dependent proteasomal degradation. Apart from ERα signaling, AKTIP loss triggers JAK2-STAT3 activation, which provides an alternative survival signal when ERα is inhibited. AKTIP-depleted MCF7 cells and ERα-positive patient-derived organoids are more resistant to ERα antagonists. Importantly, the resistance can be overcome by co-inhibition of JAK2/STAT3. Together, our results highlight the subtype-specific functional consequences of AKTIP loss and provide a mechanistic explanation for the enriched AKTIP copy-number loss in ERα-positive breast cancer.
Persistent Identifierhttp://hdl.handle.net/10722/329046
ISSN
2023 Impact Factor: 7.5
2023 SCImago Journal Rankings: 4.279
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorNg, ASN-
dc.contributor.authorZhang, SB-
dc.contributor.authorMak, VCY-
dc.contributor.authorZhou, Y-
dc.contributor.authorYuen, Y-
dc.contributor.authorSharma, R-
dc.contributor.authorLu, YL-
dc.contributor.authorZhuang, GL-
dc.contributor.authorZhao, W-
dc.contributor.authorPang, HH-
dc.contributor.authorCheung, LWT-
dc.date.accessioned2023-08-05T07:54:52Z-
dc.date.available2023-08-05T07:54:52Z-
dc.date.issued2022-12-13-
dc.identifier.citationCell Reports, 2022, v. 41, n. 11-
dc.identifier.issn2211-1247-
dc.identifier.urihttp://hdl.handle.net/10722/329046-
dc.description.abstractRecurrent deletion of 16q12.2 is observed in luminal breast cancer, yet the causal genomic alterations in this region are largely unknown. In this study, we identify that loss of AKTIP, which is located on 16q12.2, drives tumorigenesis of estrogen receptor alpha (ERα)-positive, but not ERα-negative, breast cancer cells and is associated with poor prognosis of patients with ERα-positive breast cancer. Intriguingly, AKTIP-depleted tumors have increased ERα protein level and activity. Cullin-associated and neddylation-dissociated protein 1 (CAND1), which regulates the cullin-RING E3 ubiquitin ligases, protects ERα from cullin 2-dependent proteasomal degradation. Apart from ERα signaling, AKTIP loss triggers JAK2-STAT3 activation, which provides an alternative survival signal when ERα is inhibited. AKTIP-depleted MCF7 cells and ERα-positive patient-derived organoids are more resistant to ERα antagonists. Importantly, the resistance can be overcome by co-inhibition of JAK2/STAT3. Together, our results highlight the subtype-specific functional consequences of AKTIP loss and provide a mechanistic explanation for the enriched AKTIP copy-number loss in ERα-positive breast cancer.-
dc.languageeng-
dc.publisherCell Press-
dc.relation.ispartofCell Reports-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectCP: Cancer-
dc.subjectendocrine resistance-
dc.subjectestrogen receptor-
dc.subjectluminal breast cancer-
dc.subjectprotein degradation-
dc.titleAKTIP loss is enriched in ERα-positive breast cancer for tumorigenesis and confers endocrine resistance-
dc.typeArticle-
dc.identifier.doi10.1016/j.celrep.2022.111821-
dc.identifier.pmid36516775-
dc.identifier.scopuseid_2-s2.0-85143871013-
dc.identifier.volume41-
dc.identifier.issue11-
dc.identifier.isiWOS:000901756400007-
dc.identifier.issnl2211-1247-

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