Transcriptomic analysis identifies enrichment of cAMP/PKA/CREB signaling in invasive lobular breast cancer
Abstract Objective 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...
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BMC
2024-10-01
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| Series: | Breast Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13058-024-01900-y |
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| author | Susrutha Puthanmadhom Narayanan Abdalla M. Wedn Osama Shiraz Shah Jian Chen Daniel D. Brown Priscilla F. McAuliffe Steffi Oesterreich Adrian V. Lee |
| author_facet | Susrutha Puthanmadhom Narayanan Abdalla M. Wedn Osama Shiraz Shah Jian Chen Daniel D. Brown Priscilla F. McAuliffe Steffi Oesterreich Adrian V. Lee |
| author_sort | Susrutha Puthanmadhom Narayanan |
| collection | DOAJ |
| description | Abstract Objective 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. Methods 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. Results 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. Conclusion 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. Graphical abstract |
| format | Article |
| id | doaj-art-c69028712e1246c48c93d4e17467130a |
| institution | OA Journals |
| issn | 1465-542X |
| language | English |
| publishDate | 2024-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Breast Cancer Research |
| spelling | doaj-art-c69028712e1246c48c93d4e17467130a2025-08-20T02:18:33ZengBMCBreast Cancer Research1465-542X2024-10-0126111410.1186/s13058-024-01900-yTranscriptomic analysis identifies enrichment of cAMP/PKA/CREB signaling in invasive lobular breast cancerSusrutha Puthanmadhom Narayanan0Abdalla M. Wedn1Osama Shiraz Shah2Jian Chen3Daniel D. Brown4Priscilla F. McAuliffe5Steffi Oesterreich6Adrian V. Lee7Division of Oncology, Washington UniversityWomens Cancer Research Center at UPMC Hillman Cancer Center and Magee Women’s Research InstituteWomens Cancer Research Center at UPMC Hillman Cancer Center and Magee Women’s Research InstituteWomens Cancer Research Center at UPMC Hillman Cancer Center and Magee Women’s Research InstituteInstitute for Precision Medicine, University of PittsburghDivision of Surgical Oncology, Department of Surgery, University of Pittsburgh School of MedicineWomens Cancer Research Center at UPMC Hillman Cancer Center and Magee Women’s Research InstituteWomens Cancer Research Center at UPMC Hillman Cancer Center and Magee Women’s Research InstituteAbstract Objective 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. Methods 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. Results 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. Conclusion 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. Graphical abstracthttps://doi.org/10.1186/s13058-024-01900-yInvasive lobular cancer (ILC)Invasive carcinoma—No Special Type (NST)Protein Kinase A (PKA)Cyclic AMP (cAMP)CAMP Response Element Binding Protein (CREB)Forskolin |
| spellingShingle | Susrutha Puthanmadhom Narayanan Abdalla M. Wedn Osama Shiraz Shah Jian Chen Daniel D. Brown Priscilla F. McAuliffe Steffi Oesterreich Adrian V. Lee Transcriptomic analysis identifies enrichment of cAMP/PKA/CREB signaling in invasive lobular breast cancer Breast Cancer Research Invasive lobular cancer (ILC) Invasive carcinoma—No Special Type (NST) Protein Kinase A (PKA) Cyclic AMP (cAMP) CAMP Response Element Binding Protein (CREB) Forskolin |
| title | Transcriptomic analysis identifies enrichment of cAMP/PKA/CREB signaling in invasive lobular breast cancer |
| title_full | Transcriptomic analysis identifies enrichment of cAMP/PKA/CREB signaling in invasive lobular breast cancer |
| title_fullStr | Transcriptomic analysis identifies enrichment of cAMP/PKA/CREB signaling in invasive lobular breast cancer |
| title_full_unstemmed | Transcriptomic analysis identifies enrichment of cAMP/PKA/CREB signaling in invasive lobular breast cancer |
| title_short | Transcriptomic analysis identifies enrichment of cAMP/PKA/CREB signaling in invasive lobular breast cancer |
| title_sort | transcriptomic analysis identifies enrichment of camp pka creb signaling in invasive lobular breast cancer |
| topic | Invasive lobular cancer (ILC) Invasive carcinoma—No Special Type (NST) Protein Kinase A (PKA) Cyclic AMP (cAMP) CAMP Response Element Binding Protein (CREB) Forskolin |
| url | https://doi.org/10.1186/s13058-024-01900-y |
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