Gene Polymorphisms in the Renin-Angiotensin-Aldosterone System and Breast Carcinogenesis: Is There a Connection?

Authors

  • Julian Kenrick Loh School of Medicine, Trinity College, University of Dublin, Ireland

Keywords:

Medicine

Abstract

Breast cancer is the second most common type of cancer in the world. In this article, studies are considered, which suggest a pattern may exist between polymorphisms in genes of the renin-angiotensin-aldosterone system (RAAS) and the risk of developing breast cancer. Polymorphisms of angiotensin converting enzyme (ACE), angiotensin II receptor type 1 (AGTR1) and angiotensinogen are investigated. The polymorphisms in the ACE gene cause variations in the level of ACE and therefore affect the level of angiontensin II, which is thought to contribute to breast carcinogenesis. Studies into insertion/ deletion (I/D) polymorphisms and the single nucleotide polymorphism (SNP) A-240T show that carriers of the DD genotype of the I/D polymorphism or the TT genotype of the SNP had significantly greater chances of developing breast cancer than carriers of the II or AA genotypes. SNPs in the AGTR1 gene may reduce the risk of breast cancer by either determining the binding efficiency of angiotensin II to the receptor or by interfering with the downstream signaling cascade that is required for angiotensin II to elucidate it’s carcinogenic effect. Studies on the SNPs A-168G, C-535T and T-825A are presented here and it is evident that carriers of the AA genotype, CC genotype and TT genotype may have a higher risk of developing breast cancer than carriers of GG, TT and AA genotypes respectively. A SNP, M-235T, in the angiotensinogen gene also supports the connection of polymorphisms in the RAAS system to breast cancer. This receptor may provide a useful target for pharmacological therapy in patients suffering from breast cancer. In the future polymorphisms in ACE, angiotensin II and AGT may prove to be markers for and long term use of ACE inhibitors may prove to be protective against breast cancer.

Author Biography

Julian Kenrick Loh, School of Medicine, Trinity College, University of Dublin, Ireland

Sixth Year Medicine, TCD

References

1. World Health Organization International Agency for Research on Cancer (June 2003). World Cancer Report.
2. World Health Organization (February 2006). Fact sheet No. 297: Cancer. 3.Surveillance end point reporting (SEER)
Review
http://seer.cancer.gov/statfacts/html/breast.html
4. Cavalieri E, Chakravarti D, Guttenplan J et al. (2006). Catechol estrogen quinones as initiators of breast and other human cancers: implications for biomarkers of susceptibility and cancer prevention. Biochim. Biophys. Acta. 1766;(1):63-78
5. Chaudhuri S, Cariappa A, Tang H et al. Genetic Susceptibility to Breast Cancer. Proc. Natl. Acad. Sci. 2000; 97(21):11451-4
6. American Cancer Society (2005). Breast Cancer Facts & Figures 2005-2006.
7. Inwang ER, Puddefoot JR, Brown CL et al. Angiotensin II Type 1 receptor expression in human breast tissues. Br. J. Cancer. 1997;75(9):1279-83
8.De Paepe B, Verstraeten VM, De Potter CR, Bullock GR. Increased angiotensin II type-2 receptor density in hyperplasia, DCIS and invasive carcinoma of the breast is paralleled with increased iNOS expression. Hisotchem. Cell Biol. 2002;117(1):13- 9
9. Muscella A, Greco S, Elia MG, Storelli C, Marsigliante S. Angiotensin II stimulation of Na+/K+ ATPase activity and cell growth by calcium independent pathway in MCF- 7 breast cancer cells. J. Endocrinol. 2002;173:315-23
10. Lever AF, Hole DJ, Gillis CR et al. Do inhibitors of angiotensin I converting enzyme protect against risk of cancer? Lancet. 1998;352(9123):179-84
11. Kumar and Clark. 6th ed. Elsevier limited;2006 Chapter 11:610-11
12. Koh WP, Yuan JM, Sun CL et al. Angiotensin I Converting Enzyme (ACE) Gene polymorphism and breast cancer risk among Chinese women in Singapore. Cancer Res. 2003;63:573-8
13. Gonzalez-Zuloela Ladd AM, Vasquez AA, Sayed-Tabatabaei FA et al. Angiotensin-Converting Enzyme gene insertion/deletion polymorphism and breast cancer risk. Cancer Epidemiol. Biomarkers Prev. 2005;14(9)2143-6
14. Haiman CA, Henderson SO, Bretsky P, Kolonel LN, Henderson BE. Genetic Variation in Angiotensin I Converting Enzyme (ACE) and breast cancer risk: The multiethnic cohort. Cancer Res. 2003;63:6984-7
15. Timmermans PB, Chiu AT, Herblin WF, Wong PC, Smith RD. Angiotensin II receptor subtypes. Am. J. Hypertens. 1992;5:406-10
16. Egami K, Murohara T, Shimada T et al. Role of host angiotensin II Type 1 receptors in tumour angiogenesis and growth. J. Clin. Invest. 2003;112: 67-75
17. Huang XC, Richards EM, Sumners C. Mitogen activated protein kinases in rat brain neuronal cultures are activate by angiotensin II type I receptors and inhibited by angiotensin II type II receptors. J. Biol. Chem. 1996;271:15635-41
18. Goto M, Mukoyama M, Sugawara A et al. Expression and role of angiotensin II Type 2 receptors in the kidney and mesangial cells of spontaneously hypertensive rats. Hypertens. Res. 2002;25:125-33
19. Silvestre JS, Tamarat R, Senbonmatsu T et al. Antiangiogenic effect of angiotensin II type 2 receptor in ischaemia-induced angiogenesis in mice hindlimb. Circ. Res. 2002;90:1072-109
20. Marsigliante S, Resta L, Muscella A, Vinson GP, Marzullo A, Storelli C. AT1 angiotensin II receptor subtype in the human larynx and squamous laryngeal carcinoma. Cancer Lett. 1996;110:19-27
21. Takeda H, Kondo S. Differences between squamous cell carcinoma and kerathoacanthoma in angiotensin type 1 receptor expression. Am. J. Pathol. 2001;158:1633-7
22. Koh WP, Yuan JM, Van Den Berg D, Lee HP, Yu MC. Polymorphisms in angiotensin II type 1 receptor and angiotensin I converting enzyme genes and breast cancer risk among Chinese women in Singapore. Carcinogenesis. 2005;26(2):459- 64
23. Ladd AMG, Vasquez AA, Siemes C et al. Differential roles of angiotensinogen and angiotensin receptor type 1 polymorphisms in breast cancer risk. Breast Cancer Res. Treat. 2006;101(3):299-304
24. Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I converting enzyme gene accounting for half the variance of serum enzyme levels. J. Clin. Investig. 1990;86:1343-6
25. Sayed-Tabatabaei FA, Houwing-Duistermaat JJ, van Duijn CM, Witteman JCM.
Angiotensin-converting enzyme gene polymorphism and carotid artery wall thickness: a meta analysis. Stroke. 2003;34:1634-9
26. Fraser PA, Yunis EJ, Alper CA. Excess admixture proportion of extended major histocompatability complex halotypes of Caucasian origin among rheumatoid arthritis associated halotypes in African American and Afro-Caribbeans. Ethnic Health. 1996;1:153-9
27. Knowler WC, Williams RC, Pettitt DJ, Steinberg AG. Gm3;5,13,14 and Type 2 Diabetes Mellitus: An association in American Indians with genetic admixture. Am. J. Hum. Genet. 1988;43:520-6
28. Greco S, Muscella A, Elia MG et al. Angiotensin II activates extracellular signal regulated kinases via protein C and epidermal growth factor receptor in breast cancer cells. J. Cell Physiol. Aug 2003;196(2):370-7
29. Fernandez LA, Twickler J, Mead A. Neovascularisation produced by angiotensin II. J. Lab. Clin. Med. 1985;105:141-5
30. Zafari AM, Ushio-Fukai M et al. Role of NADH/NADPH oxidase derived H2O2 in angiotensin II-induced vascular hypertrophy. Hypertension. 1998;32:488-95
31. Rueckschloos U, Quinn MT, Holtz J, Morawietz H. Dose dependent regulation of NADPH oxidase expression by angiotensin II in human endothelial cells: protective effect of angiotensin II type 1 receptor blockade in patients with coronary artery disease. Arterioscl. Thromb. Vasc. Biol. 2002;22:1845-51
32. Celerier J, Cruz A, Lamande N, Gasc JM, Corvol P. Angiotensinogen and its cleaved derivatives inhibit angiogenesis. Hypertension. 2002;39:224-8.
33. Fryzek JP, Poulsen AH, Lipworth L et al. A cohort study of antihypertensive medication use and breast cancer among Danish women. Breast Cancer Res. Treat. 2006;97(3):231-6

Downloads

Published

2008-01-01

How to Cite

Loh, J. K. (2008). Gene Polymorphisms in the Renin-Angiotensin-Aldosterone System and Breast Carcinogenesis: Is There a Connection?. Trinity Student Medical Journal, 9(1), Page 48–51. Retrieved from https://www.tsmj.ie/index.php/tsmj/article/view/1893