Angiotensin-Converting Enzyme Gene Insertion/Deletion
Polymorphism and Breast Cancer Risk
Angela M. Gonza ´lez-Zuloeta Ladd, Alejandro Arias Va ´squez, Fakhredin A. Sayed-Tabatabaei,
J.W. Coebergh, Albert Hofman, Omer Njajou, Bruno Stricker, and Cornelia van Duijn
Epidemiology and Biostatistics Department, Erasmus Medical Center, Rotterdam, the Netherlands
Background: The renin-angiotensin system plays an im-
portant 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) polymor-
phism 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
Methods: The ACE I/D polymorphism was genotyped
in 4,117 women participants in the Rotterdam Study.
Baseline information was obtained through a question-
naire. We conducted a logistic regression and survival
analysis to assess the risk of breast cancer by the ACE
Results: 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
menopause, hormone replacement therapy, and hypertension.
Our survival analysis showed that the cancer-free survival
was significantly reduced in DD compared with II carriers
Conclusions: Our results suggest that the ACE I/D poly-
morphism plays an important role in breast cancer risk
and disease-free survival in Caucasian postmenopausal
(Cancer Epidemiol Biomarkers Prev 2005;14(9):
Breast cancer presents a serious public health risk in both
developed and developing countries. With 1 million new cases
diagnosed in the world annually, it accounts for 18% of all
female malignancies (1, 2). Risk factors for this disease vary
from lifestyle to genetic factors (3), which are estimated to
account for 15% to 25% of the cases (4). Germ line mutations in
high-penetrance genes, such as BRCA 1 and BRCA 2, explain
<5% of all breast cancer cases (4). Most likely, the genetic
susceptibility to breast cancer is explained by multiple highly
penetrant mutations and a larger number of low penetrance
mutations (5). The genes involved in breast cancer are expected
to be responsible for key processes in cell growth regulation
and cell proliferation, including angiogenesis (6). One of the
newly studied angiogenic and growth factors is angiotensin II
(7), which has a wide spectrum of target tissues, including
breast epithelial cells. It has a variety of functions, acting as a
growth factor both in normal and cancer epithelial breast cells
and promoting angiogenesis (7, 8). Angiotensin II is converted
from angiotensin I by the angiotensin-converting enzyme
(ACE). Studies conducted to assess the role of ACE and ACE
inhibitors in both breast cancer and cancer in general show
contradicting results. Whereas ACE inhibitors have been
shown to block the processes of angiogenesis and tumor
growth both in vivo and in vitro (9, 10), findings on the
protective effect of ACE inhibitors on cancer still remain
inconsistent. Whereas Lever et al. (11) found a decreased risk of
cancer in patients taking ACE inhibitors, Li et al. (12) and Friis
et al. (13) showed no protective effect of these drugs. An
alternative way to study the role of ACE in cancer is
to study the gene encoding for this enzyme. The ACE gene,
which is located in chromosome 17q23, has many polymor-
phisms. The most commonly studied is a 287 bp Alu insertion/
deletion (I/D) polymorphism in intron 16 that accounts for 50%
of the variability in circulating ACE levels (14-16) and has been
shown to be in complete linkage disequilibrium with the
putative ACE-linked quantitative trait locus in Caucasians
(15, 16). Furthermore, Koh et al. (17) showed that Chinese
women who carried the I allele of the ACE I/D polymorphism
had lower risk of developing breast cancer.
In this study, we evaluated the relationship of the I/D
polymorphism in the ACE gene to breast cancer risk in a
population-based study of Caucasian postmenopausal women.
Patients and Methods
Study Population. Our study is part of the Rotterdam
Study, a population-based follow-up study of determinants of
diseases in the elderly. All inhabitants of Ommoord, a suburb
of Rotterdam, ages 55 years or older were invited to
participate, of whom 7,983 agreed (78.1%). The design of the
study has been previously described (18). Informed consent
was obtained from all subjects, and the Medical Ethics
Committee of the Erasmus Medical Center approved the
study. The study population consisted of all 4,878 female
Cancer Epidemiol Biomarkers Prev 2005;14(9). September 2005
on November 6, 2015. © 2005 American Association for Cancer cebp.aacrjournals.org Downloaded from
Received 1/18/05; revised 6/15/05; accepted 6/22/05.
Grant support: The Netherlands Organization for Scientific Research grant 904-61-196, EUR
Fellowship (O. Njajou), and Centre of Medical Systems Biology grant 297-2003 (A. Arias
Vasquez). The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus
University Rotterdam; the Netherlands Organization for Scientific Research; the Netherlands
Organization for Health Research and Development; Research Institute for Diseases in the
Elderly; Ministry of Education, Culture and Science; Ministry of Health, Welfare, and Sports;
European Commission (DG XII); and Municipality of Rotterdam.
The costs of publication of this article were defrayed in part by the payment of page charges.
This article must therefore be hereby marked advertisement in accordance with 18 U.S.C.
Section 1734 solely to indicate this fact.
Note: A. Arias Va ´squez contributed with the design of the study and also participated in the
data analyses along with F.A. Sayer-Tabatabaei and C. van Duijn, who participated in the
design and writing of the manuscript. J.W. Coebergh, B. Stricker, and A. Hofman aided in the
data collection and the writing of the manuscript as well.
Requests for reprints: Cornelia van Duijn, Department of Epidemiology and Biostatistics,
Erasmus Medical Center, P.O. Box 1738, 3000 DR Rotterdam, the Netherlands.
Phone: 31-10-408-7394; Fax: 31-10-408-9406. E-mail: firstname.lastname@example.org
Copyright D 2005 American Association for Cancer Research.