HOXA5-Mediated Stabilization of IκBα Inhibits the NF-κB Pathway and Suppresses Malignant Transformation of Breast Epithelial Cells.
Animals
Cell Line, Tumor
Cell Transformation, Neoplastic
/ genetics
Class I Phosphatidylinositol 3-Kinases
/ metabolism
Epithelial Cells
/ metabolism
Homeodomain Proteins
/ genetics
Interleukin-6
/ metabolism
Mice
NF-KappaB Inhibitor alpha
/ genetics
NF-kappa B
/ metabolism
Transcription Factors
/ genetics
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
17 10 2022
17 10 2022
Historique:
received:
23
12
2021
revised:
01
06
2022
accepted:
22
08
2022
pubmed:
28
9
2022
medline:
19
10
2022
entrez:
27
9
2022
Statut:
ppublish
Résumé
HOXA5 is a transcription factor and tumor suppressor that promotes differentiation of breast epithelial cells and is frequently lost during malignant transformation. HOXA5 loss alone, however, does not confer tumorigenicity. To determine which molecular alterations combined with loss of HOXA5 expression can transform cells, we examined isogenic derivatives of a nonmalignant breast epithelial cell line containing knock-in or knockout mutations in key breast cancer genes. Knockdown (KD) of HOXA5 in cells harboring double knock-in (DKI) of mutated PIK3CA (E545K) and HER2 (V777L) induced epithelial-mesenchymal transition and migration and promoted invasive tumor outgrowth within mouse mammary ducts. The NF-κB pathway was significantly upregulated in DKI cells following HOXA5 KD. HOXA5 KD upregulated multiple NF-κB target genes, including IL6. IκBα protein, but not RNA, expression was reduced in HOXA5-KD cells. HOXA5 bound and stabilized IκBα, forming a nuclear HOXA5-IκBα complex. Chromatin immunoprecipitation sequencing database queries revealed that HOXA5 and IκBα are co-enriched at 528 genomic loci. In patients with breast cancer, high coexpression of HOXA5 and IκBα conferred a significantly better overall and progression-free survival. Collectively, these data suggest that HOXA5 suppresses malignancy in breast epithelial cells by blunting NF-κB action via stabilization of its inhibitor IκBα. Loss of HOXA5 reduces IκBα stability and increases NF-κB signaling to exacerbate breast cancer aggressiveness, providing new insights into the tumor suppressor functions of HOXA5.
Identifiants
pubmed: 36166646
pii: 709474
doi: 10.1158/0008-5472.CAN-21-4277
pmc: PMC9588663
mid: NIHMS1833867
doi:
Substances chimiques
Homeodomain Proteins
0
Hoxa5 protein, mouse
0
Interleukin-6
0
NF-kappa B
0
Transcription Factors
0
NF-KappaB Inhibitor alpha
139874-52-5
Class I Phosphatidylinositol 3-Kinases
EC 2.7.1.137
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3802-3814Subventions
Organisme : NCI NIH HHS
ID : P50 CA103175
Pays : United States
Informations de copyright
©2022 American Association for Cancer Research.
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