Angiotensin-converting enzyme gene insertion/deletion polymorphism and breast cancer risk
ABSTRACT The renin-angiotensin system plays an important role in homeostasis and lately, its main effector, angiotensin II, has been attributed with angiogenic and growth factor actions in the breast tissue. Previous studies have shown that the insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene accounts for the variability of ACE plasma concentrations. The use of ACE inhibitors and the ACE I/D polymorphism may be linked to breast cancer risk. In this study, we evaluate the relationship of the ACE I/D polymorphism with breast cancer risk in Caucasian postmenopausal women.
The ACE I/D polymorphism was genotyped in 4,117 women participants in the Rotterdam Study. Baseline information was obtained through a questionnaire. We conducted a logistic regression and survival analysis to assess the risk of breast cancer by the ACE genotype.
The DD carriers showed a significantly increased risk of developing breast cancer when compared with the II carriers (odds ratio, 1.86; 95% confidence interval, 1.06-3.27; P = 0.03). This association remained after adjusting for other risk factors, including body mass index, age at menarche, age at menopause, hormone replacement therapy, and hypertension. Our survival analysis showed that the cancer-free survival was significantly reduced in DD compared with II carriers (hazard ratio, 1.80; 95% confidence interval, 1.07-3.01; P = 0.03).
Our results suggest that the ACE I/D polymorphism plays an important role in breast cancer risk and disease-free survival in Caucasian postmenopausal women.
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ABSTRACT: The association between the polymorphism of the angiotensin-converting enzyme (ACE) gene and breast cancer risk has been extensively studied, however, the studies about the prognostic factors and ACE gene polymorphism are limited in number. Our aims were to analyze the distribution of the insertion/deletion (I/D) polymorphism of the ACE gene in Turkish premenopausal patients with breast cancer, which is more aggressive than the postmenopausal counterpart, and to assess whether DD genotype is associated with poor prognostic factors. The DD genotype has been shown to be associated with the increased serum and tissue levels of ACE, compared to those in II and ID genotypes. ACE genotypes were determined by polymerase chain reaction in 44 Turkish premenopausal patients with breast cancer and in 46 age-matched healthy premenopausal women. ACE genotypes are distributed in patients and control subjects as follows; DD is present in 25 (56.8%), ID in 17 (38.6%), and II in 2 (4.5%) patients, and DD in 28 (60.9%), ID in 12 (26.1%), and II in 6 (13.0%) healthy subjects, respectively. D and I alleles were found in 76.1% and 23.9% of the patients, while 73.9% and 26.1% in healthy subjects, respectively. In breast cancer patients, no significant association was observed between the ACE genotypes and poor prognostic factors, such as negative hormone receptor status, histological grade, lymph node involvement, higher number of lymph node metastases, and c-erb B2 overexpression, except that tumor size greater than 2 cm is associated with DD genotype (p = 0.02). Thus, ACE may influence the local tumor growth of breast cancer in premenopausal patients.The Tohoku Journal of Experimental Medicine 11/2006; 210(2):109-16. DOI:10.1620/tjem.210.109 · 1.28 Impact Factor
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ABSTRACT: Local bone marrow renin-angiotensin system (RAS) is an autocrine-paracrine system affecting normal and neoplastic hema-topoiesis. Angiotensin converting enzyme (ACE) converts angiotensinogen-I to its physiologically active peptide angiotensin-II, which stimulates proliferation and differentiation of hematopoietic stem cells through angiotensin II type 1 receptors. We investigated the ACE insertion/deletion (I/D) gene polymorphisms in patients with hematological malignancies including acu-te and chronic leukemia, myelodysplastic syndrome and multiple myeloma. Our results showed that 80.4% of the patients represented ID/II genotype, whereas it was 55.9% of the control group and 3.2 fold increased disease risk in the existence of insertion allele (ID/II). This is the first study demonstrating possible effects of ACE I/D gene polymorphism of the local bo-ne marrow RAS components on leukemic hematopoiesis. Keywords: Angiotensin converting enzyme, Local renin-angiotensin system, ACE I/D gene polymorphism, Angiotensin II, Leukemic hematopoiesis ÖZET Lösemik Hematopoezde Kemik ‹li¤i Anjiotensin II Tip I Reseptör Gen ve Anjiotensin Dönüfltürücü Enzim (ACE) ‹nsersiyon/Delesyon (I/D) Gen Polimorfizmleri Lokal kemik ili¤i renin anjiotensin sistemi (RAS) normal ve neoplastik hematopoezi etkileyen otokrin ve parakrin bir sistemdir. Anjiotensin dönüfltürücü enzim (ACE) anjiotensinojen-I'i kendisinin fizyolojik olarak aktif peptide olan anjiotensin II'ye dönüfl-türür ki, bu hemetopoetik kök hücrelerin ço¤almas›n› ve farkl›laflmas›n› anjiotensin tip 1 reseptörleri üzerinden uyar›r. Biz ACE insersyon/delesyon gen polimorfizmlerini akut ve kronik lösemi, myelodisplastik sendrom ve multiple myeloma gibi hemato-lojik malignasili hastalarda araflt›rd›k. Çal›flma sonuçlar›m›za göre hastalar›n % 80.4'ü ID/II genotipi gösterirken bu oran kont-rol grubunda % 55.9 olarak bulundu ve insersiyon alleli varl›¤›nda (ID/II) 3.2 kat artm›fl hastal›k riski saptand›. Bu lokal ke-mik il¤i RAS üyelerinden ACE'nin I/D gen polimorfizminin lösemik hematopoezdeki olas› etkisini gösteren ilk çal›flmad›r.
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ABSTRACT: Angiotensin II (Ang II), a main effector peptide in the renin-angiotensin system (RAS), plays a fundamental role as a vasoconstrictor in controlling cardiovascular function and renal homeostasis. Ang II also acts as a growth promoter or angiogenic factor via type 1 angiotensin II receptors (AT1Rs) in certain tumour cell lines. Recent studies have shown the activation of the local RAS in various tumour tissues, including the abundant generation of Ang II by angiotensin-converting enzyme (ACE) and the upregulation of AT1R expression. Thus, considerable attention has been paid to the role of the RAS in cancer and its blockade as a new approach to the treatment of cancer. There is increasing evidence that the Ang II-AT1R system is involved in tumour growth, angiogenesis and metastasis in experimental models, suggesting the therapeutic potential of an ACE inhibitor and AT1R blocker, both of which have been used as antihypertensive drugs. In addition, specific Ang II-degrading enzymes are expressed in tumours and play a regulatory role in cell proliferation and invasion. This review focuses on the role of the Ang II-AT1R system in solid tumours, particularly in the progression of gynaecological cancer, and presents the clinical potential of manipulating the angiotensin system as a novel and promising strategy for cancer treatment.Expert opinion on biological therapy 04/2006; 6(3):243-55. DOI:10.1517/147125126.96.36.199 · 3.65 Impact Factor