AGTR1 overexpression defines a subset of breast cancer and confers sensitivity to losartan, an AGTR1 antagonist
- PMID: 19487683
- PMCID: PMC2689309
- DOI: 10.1073/pnas.0900351106
AGTR1 overexpression defines a subset of breast cancer and confers sensitivity to losartan, an AGTR1 antagonist
Abstract
Breast cancer patients have benefited from the use of targeted therapies directed at specific molecular alterations. To identify additional opportunities for targeted therapy, we searched for genes with marked overexpression in subsets of tumors across a panel of breast cancer profiling studies comprising 3,200 microarray experiments. In addition to prioritizing ERBB2, we found AGTR1, the angiotensin II receptor type I, to be markedly overexpressed in 10-20% of breast cancer cases across multiple independent patient cohorts. Validation experiments confirmed that AGTR1 is highly overexpressed, in several cases more than 100-fold. AGTR1 overexpression was restricted to estrogen receptor-positive tumors and was mutually exclusive with ERBB2 overexpression across all samples. Ectopic overexpression of AGTR1 in primary mammary epithelial cells, combined with angiotensin II stimulation, led to a highly invasive phenotype that was attenuated by the AGTR1 antagonist losartan. Similarly, losartan reduced tumor growth by 30% in AGTR1-positive breast cancer xenografts. Taken together, these observations indicate that marked AGTR1 overexpression defines a subpopulation of ER-positive, ERBB2-negative breast cancer that may benefit from targeted therapy with AGTR1 antagonists, such as losartan.
Conflict of interest statement
The authors declare no conflict of interest.
Figures
Similar articles
-
Overexpression of angiotensin II type 1 receptor in breast cancer cells induces epithelial-mesenchymal transition and promotes tumor growth and angiogenesis.Biochim Biophys Acta. 2016 Jun;1863(6 Pt A):1071-81. doi: 10.1016/j.bbamcr.2016.03.010. Epub 2016 Mar 11. Biochim Biophys Acta. 2016. PMID: 26975580
-
AGTR1 as a therapeutic target in ER-positive and ERBB2-negative breast cancer cases.Cell Cycle. 2009 Dec;8(23):3794-5. doi: 10.4161/cc.8.23.9976. Cell Cycle. 2009. PMID: 19934656 Free PMC article. No abstract available.
-
Dual targeting of angiotensin receptors (AGTR1 and AGTR2) in epithelial ovarian carcinoma.Gynecol Oncol. 2014 Oct;135(1):108-17. doi: 10.1016/j.ygyno.2014.06.031. Epub 2014 Jul 9. Gynecol Oncol. 2014. PMID: 25014541
-
Losartan in diabetic nephropathy.Expert Rev Cardiovasc Ther. 2004 Jul;2(4):473-83. doi: 10.1586/14779072.2.4.473. Expert Rev Cardiovasc Ther. 2004. PMID: 15225108 Review.
-
Role and therapeutic potential of G-protein coupled receptors in breast cancer progression and metastases.Eur J Pharmacol. 2015 Sep 15;763(Pt B):178-83. doi: 10.1016/j.ejphar.2015.05.011. Epub 2015 May 14. Eur J Pharmacol. 2015. PMID: 25981295 Free PMC article. Review.
Cited by
-
Heart failure pharmacotherapy and cancer: pathways and pre-clinical/clinical evidence.Eur Heart J. 2024 Apr 7;45(14):1224-1240. doi: 10.1093/eurheartj/ehae105. Eur Heart J. 2024. PMID: 38441940 Free PMC article. Review.
-
Nanofabrications of Erythrocyte Membrane-Coated Telmisartan Delivery System Effective for Radiosensitivity of Tumor Cells in Mice Model.Int J Nanomedicine. 2024 Feb 16;19:1487-1508. doi: 10.2147/IJN.S441418. eCollection 2024. Int J Nanomedicine. 2024. PMID: 38380147 Free PMC article.
-
Synergistic suppressive effects on triple-negative breast cancer by the combination of JTC-801 and sodium oxamate.Am J Cancer Res. 2023 Oct 15;13(10):4661-4677. eCollection 2023. Am J Cancer Res. 2023. PMID: 37970352 Free PMC article.
-
The renin-angiotensin-aldosterone system (RAAS) signaling pathways and cancer: foes versus allies.Cancer Cell Int. 2023 Oct 27;23(1):254. doi: 10.1186/s12935-023-03080-9. Cancer Cell Int. 2023. PMID: 37891636 Free PMC article. Review.
-
The AT1/AT2 Receptor Equilibrium Is a Cornerstone of the Regulation of the Renin Angiotensin System beyond the Cardiovascular System.Molecules. 2023 Jul 18;28(14):5481. doi: 10.3390/molecules28145481. Molecules. 2023. PMID: 37513355 Free PMC article. Review.
References
-
- King CR, Kraus MH, Aaronson SA. Amplification of a novel v-erbB-related gene in a human mammary carcinoma. Science. 1985;229:974–976. - PubMed
-
- Slamon DJ, et al. Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177–182. - PubMed
-
- Di Fiore PP, et al. erbB-2 is a potent oncogene when overexpressed in NIH/3T3 cells. Science. 1987;237:178–182. - PubMed
-
- Piccart-Gebhart MJ, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659–1672. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Molecular Biology Databases
Research Materials
Miscellaneous