Transcriptomic analysis identifies enrichment of cAMP/PKA/CREB signaling in invasive lobular breast cancer.
Humans
Female
Breast Neoplasms
/ genetics
Carcinoma, Lobular
/ genetics
Signal Transduction
Cyclic AMP Response Element-Binding Protein
/ metabolism
Cyclic AMP
/ metabolism
Gene Expression Profiling
Cyclic AMP-Dependent Protein Kinases
/ metabolism
Gene Expression Regulation, Neoplastic
Transcriptome
Cell Line, Tumor
Biomarkers, Tumor
/ genetics
CAMP Response Element Binding Protein (CREB)
Cyclic AMP (cAMP)
Forskolin
Invasive carcinoma—No Special Type (NST)
Invasive lobular cancer (ILC)
Protein Kinase A (PKA)
Journal
Breast cancer research : BCR
ISSN: 1465-542X
Titre abrégé: Breast Cancer Res
Pays: England
ID NLM: 100927353
Informations de publication
Date de publication:
30 Oct 2024
30 Oct 2024
Historique:
received:
04
07
2024
accepted:
03
10
2024
medline:
31
10
2024
pubmed:
31
10
2024
entrez:
31
10
2024
Statut:
epublish
Résumé
Invasive lobular breast cancer (ILC) is the most common special type of breast cancer and has unique clinicopathological and molecular hallmarks that differentiate it from the more common invasive carcinoma-no special type (NST). Despite these differences, ILC and NST are treated as a single entity and there is a lack of ILC-targeted therapies. To fill this gap, we sought to identify novel molecular alterations in ILC that could be exploited for targeted therapies. Differential gene expression and Geneset Enrichment and Variation analyses were performed on RNA-seq data from three large public breast cancer databases-the Sweden Cancerome Analysis Network-Breast (SCAN-B; luminal A ILC N = 263, luminal A NST N = 1162), The Cancer Genome Atlas (TCGA; luminal A ILC N = 157, luminal A NST N = 307) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC; luminal A ILC N = 65, luminal A NST N = 533). Pathways enriched in overlapping differentially expressed genes from these datasets were clustered using Jaccard similarity to identify pathways enriched in ILC. The cAMP/PKA/CREB signaling was studied in ILC, ILC-like and NST cell lines and patient-derived organoids (PDOs) using forskolin, an activator of the pathway. Clinicopathological features of patients with ILC and NST in SCAN-B were similar to prior population-based studies. There was a consistent pattern of up-regulation of cAMP/PKA/CREB related signaling in ILC compared to NST in SCAN-B, TCGA and METABRIC. Treatment with forskolin resulted in a greater increase in phospho-CREB in ILC cell lines and organoids than NST. CRISPR deletion of CDH1 in NST cell lines did not alter response of cells to forskolin as measured by phospho-CREB. Forskolin treatment caused growth inhibition in ILC and NST, with ILC cell lines being more sensitive to forskolin-mediated growth inhibition. In three separate datasets, cAMP/PKA/CREB signaling was identified to be higher in ILC than NST. This in silico finding was validated in cell line and organoid models. Loss of CDH1 was not sufficient to mediate this phenotype. Future studies should investigate the mechanisms for differential cAMP/PKA/CREB signaling and the potential for therapeutic targeting in patients with ILC.
Identifiants
pubmed: 39478577
doi: 10.1186/s13058-024-01900-y
pii: 10.1186/s13058-024-01900-y
doi:
Substances chimiques
Cyclic AMP Response Element-Binding Protein
0
Cyclic AMP
E0399OZS9N
Cyclic AMP-Dependent Protein Kinases
EC 2.7.11.11
CREB1 protein, human
0
Biomarkers, Tumor
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
149Informations de copyright
© 2024. The Author(s).
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