A Gagliardi

A Grimberg

Alesse R dos Santos

B Fisher

BB da Silva

Benedito B da Silva

C Laban

Cleicilene G Pires

CS Mantzoros

Daniel S Moita

DE Rollison

Edílson C Sousa-Junior

EJ Duschek

F Vignon

G Furstenberger

H Gronbaek

H Yu

J Eng-Wong

KL Blackwell

MJ Campbell

P Toniolo

PD Delmas

Pedro V Lopes-Costa

R Torrisi

R Winston

SE Hankinson

SR Cummings

VG Vogel

English

PubMed

Springer - Publisher Connector

BioMed Central
International Seminars in Surgical 
Oncology
ssOpen AcceResearch
Evaluation of insulin-like growth factor-I in postmenopausal women 
with breast cancer treated with raloxifene
Benedito B da Silva*, Daniel S Moita, Cleicilene G Pires, Edílson C Sousa-
Junior, Alesse R dos Santos and Pedro V Lopes-Costa
Address: Department of Gynecology, Federal University of Piauí, Teresina, Piauí, Brazil
Email: Benedito B da Silva* - beneditoborges@globo.com; Daniel S Moita - daniel.moita@hotmail.com; 
Cleicilene G Pires - cleicilene@ig.com.br; Edílson C Sousa-Junior - edmilnew@yahoo.com; Alesse R dos Santos - alesse@terra.com.br; 
Pedro V Lopes-Costa - pvlcosta@ig.com.br
* Corresponding author    
Abstract
Background: The objective of this study was to evaluate serum IGF-I levels in postmenopausal
women with breast cancer treated primarily with raloxifene.
Methods: Twenty-two postmenopausal patients with operable, stage I or II, estrogen receptor-
positive carcinomas participated in this study. Following confirmation of diagnosis, the patients
received 60 mg of raloxifene for 28 days prior to definitive surgery. Blood samples were collected
for evaluation of serum IGF-I levels prior to initiating medication and following a 28-day treatment
course. Student's t-test for paired samples was used in the statistical analysis. Significance was
established at p < 0.05.
Results: Mean serum IGF-I levels pre- and post-raloxifene treatment were 143.7 ± 9.7 ng/ml and
94.8 ± 7.6 ng/ml, respectively. This reduction in serum IGF-I levels following treatment with
raloxifene was statistically significant (p < 0.001).
Conclusion: Raloxifene significantly reduced serum IGF-I levels in postmenopausal women with
breast cancer.
Background
Insulin-like growth factor-I (IGF-I) is produced princi-
pally in the liver upon stimulation by GH and plays an
important role in promoting normal and neoplastic cell
proliferation [1-8]. Insulin-like growth factors I and II are
almost exclusively bound to IGF binding proteins
(IGFBPs), less than 1% circulating freely [7]. There are six
types of IGFBP; however, more than 90% of all circulating
IGF-I is bound to IGF binding protein-3 (IGFBP-3)
[7,9,10]. IGFBP-3 inhibits the action of IGF-I at cell level
by competitively binding IGF-I and thereby preventing it
from binding to the IGF-I receptor [7].
The IGF system is currently recognized as a risk factor for
the principal types of epithelial cancer [11,12]. Studies
have shown an association of increased serum levels of
IGF-I and decreased levels of IGFBP-3 with an increased
risk of breast cancer in premenopausal women [13,14],
suggesting that these patients may benefit from measures
able to reduce serum IGF-I levels and increase IGFBP-3
levels. Nevertheless, a few studies have shown that some
Published: 23 July 2007
International Seminars in Surgical Oncology 2007, 4:18 doi:10.1186/1477-7800-4-18
Received: 16 May 2007
Accepted: 23 July 2007
This article is available from: http://www.issoonline.com/content/4/1/18
© 2007 da Silva et al; licensee BioMed Central Ltd. 
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), 
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Page 1 of 4
(page number not for citation purposes)
International Seminars in Surgical Oncology 2007, 4:18 http://www.issoonline.com/content/4/1/18therapeutic strategies have succeeded in reducing serum
IGF-I levels but without altering IGFBP-3 levels [2,7]. Ster-
oidal and non-steroidal antiestrogens have been previ-
ously shown to inhibit the growth of estrogen receptor
(ER)-positive cells, not only by acting as competitors of
hormone agonists on nuclear receptors, but also by pre-
venting the mitogenic action of the growth factor in the
total absence of estrogens [15].
Significantly reduced serum IGF-I levels have also been
reported in postmenopausal women with breast cancer
treated primarily with tamoxifen [1,3]. However,
tamoxifen exerts an estrogen-agonistic effect on the
endometrium and when used for long periods of time
increases the risk of endometrial carcinoma 3–4-fold in
postmenopausal women [16], a fact that has triggered a
search for alternative SERMS for the chemoprevention
and treatment of breast cancer [17]. Raloxifene is a sec-
ond-generation SERM that was initially approved by the
US Food and Drug Administration for the prevention and
treatment of osteoporosis; however, it was found to exert
an antiestrogenic effect on the breast without stimulating
the endometrium [18,19]. This fact was confirmed in the
recently published Study of Tamoxifen and Raloxifene
(STAR) trial, which showed that raloxifene is as effective
as tamoxifen in reducing the risk of invasive breast cancer,
as well as reducing the risk of endometrial carcinoma
compared to tamoxifen [20].
To the best of our knowledge, only one study published in
the literature has evaluated the effects of raloxifene,
administered for a period of 14 days prior to surgery, on
serum IGF-I levels as a primary treatment for breast cancer
in postmenopausal women [2]. It is possible that women
may benefit from the use of raloxifene over a longer
period of time, both in chemoprevention and in the treat-
ment of breast cancer. Therefore, in view of the paucity of
reports in the literature on the primary effects of
raloxifene on serum IGF-I levels in postmenopausal
women with breast cancer, we decided to carry out the
present study in which medication was administered for
28 days prior to definitive surgery.
Patients and Methods
Patients
The protocol of this study received the approval of the
Institutional Review Board of the Federal University of
Piauí. All volunteers gave their signed, informed consent
prior to initiation of the study. Twenty-two postmenopau-
sal women in amenorrhea for at least two years, who had
sought medical care at the Mastology Department of the
Federal University of Piauí and who had been diagnosed
with operable, estrogen-receptor-positive, invasive ductal
carcinoma for which they had received no prior treatment,
were enrolled to this study. Following hematoxylin-eosin
staining and confirmation of the diagnosis of invasive
ductal carcinoma, the paraffin blocks containing the sam-
ples underwent histochemical analysis to evaluate estro-
gen receptor status. Tumors with nuclear staining
measured semiquantitatively as high (>10% immunore-
active cells) were considered positive. Patients with endo-
crinopathies, those in use of hormonal medication or any
other medication that could interfere with serum IGF-I
levels were excluded from the study. Tumors ranged from
2 to 5 cm in size, stages I or II. Patients were aged 47 to 87
years (mean 63 years).
Treatment
The patients received 60 mg of raloxifene/day for a period
of 28 days prior to definitive surgery, starting at the time
of confirmation of the diagnosis following tumor biopsy.
Sample collections
For the analysis of serum IGF-I levels, two fasting blood
samples were taken, one at baseline, i.e. prior to the initi-
ation of raloxifene therapy, and the second after a 28-day
course of the treatment. Plasma was separated by centrif-
ugation and aliquots were stored at -20°C until assayed.
All tests were carried out by a professional who was
blinded with respect to patient identification.
Assay method
For the analysis of the serum concentrations of insulin-
like growth factor-I, the automated immunoassay ana-
lyzer, DPC Immulite 2000 (DPC Inc., Los Angeles, USA)
was used, and methodology consisted of a solid-phase
enzyme-labeled chemiluminescent immunometric assay.
Analytic sensitivity was 20 ng/ml and the reference values
varied according to age.
Statistical methods
Comparison of the means of serum IGF-I levels measured
prior to and after 28 days of raloxifene use was carried out
using Student's t-test for paired samples. Statistical signif-
icance was established at p < 0.05.
Results
Mean pretreatment serum IGF-I level was 143.7 ± 9.7 ng/
ml, whereas mean post-treatment serum IGF-I level was
94.8 ± 7.6 ng/ml (Table 1). This difference was statistically
significant (p < 0.001). The box-plot clearly shows a
reduction in the median serum levels of IGF-I evaluated
28 days after the use of raloxifene in postmenopausal
patients with breast cancer (Figure 1).
Discussion
Insulin-like growth factors are potent mitogens for the
proliferation of breast cancer cells [1]. Insulin-like growth
factor-I is a potent mitogen for breast cancer cell lines and
it is now accepted that elevated IGF-I levels are a risk factorPage 2 of 4
(page number not for citation purposes)
International Seminars in Surgical Oncology 2007, 4:18 http://www.issoonline.com/content/4/1/18for breast cancer in the premenopause [3]. Therefore,
women at risk of breast cancer or patients with neoplasia
may benefit either preventively or therapeutically from
strategies to reduce serum IGF-I levels [2]. SERMs have
been shown to reduce both circulating and microenviron-
mental levels of IGF-I, thereby suppressing IGF-induced
growth of both ER-positive and ER-negative breast cancer
cells [1]. Nevertheless, the adverse effects of tamoxifen,
principally stimulation of the endometrium, have evoked
interest in studying other SERMS that may have a lesser
negative effect or no negative effect on the endometrium
and a similar or greater efficacy in chemoprevention or in
the treatment of breast carcinoma [16,17].
In the present study, raloxifene, at a dose of 60 mg/day for
28 days, significantly reduced serum IGF-I levels in post-
menopausal women with estrogen receptor-positive
breast carcinoma. The schedule of 28 days of use of the
medication by postmenopausal women prior to surgery
was chosen with the intention of administering the drug
for a longer period of time; however without delaying
definitive surgery, 28 days being the mean time in our
institute between the first consultation and surgery. In
addition, the dose of 60 mg of raloxifene was chosen
because it is the most commonly used dose for the preven-
tion and treatment of osteoporosis and in clinical trials in
the chemoprevention of breast cancer [19]. Serum levels
of IGBP-3 were not evaluated; however some studies have
shown no changes following the administration of
raloxifene, except a decrease in the IGF-I/IGFBP-3 molar
ratio following raloxifene treatment [2]. Our study was
not placebo-controlled, and therefore subjects were not
randomized to a treatment regimen. A placebo-controlled
study would have had distinct design advantages over the
study described here; however, controversies on the ethi-
cal implications of such trials have been the subject of
recent collaborative reports [3,21].
Our findings of a reduction in serum IGF-I levels in post-
menopausal women with breast cancer following treat-
ment with raloxifene are in agreement with data
published by other investigators [2]. The study of serum
IGF-I levels only in women with estrogen receptor-posi-
tive tumors does not appear to be an issue since SERMs
reduce serum IGF-I levels both in women with estrogen
receptor-positive and negative tumors [1,22]. Apart from
their main action via estrogen receptors, SERMs possess
numerous other plausible mechanisms for controlling
tumor growth, such as binding to protein kinase C and
inhibiting angiogenesis [22,23]. An experimental study
has shown angiogenesis inhibition in an estrogen recep-
tor-negative animal model, suggesting that the antiang-
iogenic effects of SERMs are partially due to mechanisms
that do not depend on estrogen receptors [24]. In addi-
tion, reports from other experimental studies have sug-
gested the possibility that the action of antiestrogens does
not occur only via estrogen receptors but also by direct
inhibition of growth factors [22], which may explain the
response of some estrogen receptor-negative breast
tumors to SERMs.
Interest in the role of the insulin-like growth factor (IGF)
axis in carcinogenesis has grown following the finding of
elevated serum levels of insulin-like growth factor-I in
association with the principal forms of epithelial cancer
[9,12]. In addition, IGF-I is a systemic hormone with
potent anti-apoptotic and mitogenic properties that may
influence the proliferative behavior of breast cells [14].
Raloxifene has been shown to be effective in inhibiting
cell proliferation both in normal and in neoplastic breast
tissue [17]. According to one recent report, the drug signif-
icantly reduced Ki-67 antigen expression in the breast tis-
sue of premenopausal women [17]. Finally, the reduction
in serum IGF-I levels by raloxifene in postmenopausal
Boxplot of serum IGF-I levels measured prior to and follow-ing 28 days of raloxifene tr at nt in post-menopausal w men with b east ca cFi ure 1
Boxplot of serum IGF-I levels measured prior to and follow-
ing 28 days of raloxifene treatment in post-menopausal 
women with breast cancer.
Table 1: Descriptive measurements of IGF-I measured prior to and following 28 days of raloxifene treatment
SerumIGF-I levels Mean S. E. Minimum Maximum
Before treatment 143.7 9.7 77.1 224.0
After treatment 94.8* 7.6 41.9 190.0
* The difference was statistically significant (p < 0.001).Page 3 of 4
(page number not for citation purposes)
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women with breast cancer supports the need to conduct
further clinical trials on adjuvant therapy and chemopre-
vention with raloxifene.
References
1. Winston R, Kao PC, Kiang DT: Regulation of insulin-like growth
factors by antiestrogen.  Breast Cancer Res Treat 1994, 31:107-115.
2. Torrisi R, Baglietto L, Johansson H, Veronesi G, Bonanni B, Guerrieri-
Gonzaga A, Ballardini B, Decensi A: Effect of raloxifene on IGF-I
and IGFBP-3 in postmenopausal women with breast cancer.
Br J Cancer 2001, 85:1838-1841.
3. Campbell MJ, Woodside JV, Secker-Walker J, Titcomb A, Leathem AJ:
IGF status is altered by tamoxifen in patients with breast
cancer.  Mol Pathol 2001, 54:307-310.
4. Eng-Wong J, Hursting SD, Venzon D, Perkins SN, Zujewski JA: Effect
of raloxifene on insulin-like growth factor-I, insulin-like
growth factor binding protein-3, and leptin in premenopau-
sal women at high risk for developing breast cancer.  Cancer
Epidemiol Biomarkers Prev 2003, 12:1468-1473.
5. Gronbaek H, Tanos V, Meirow D, Peretz T, Raz I, Flyvbjerg A: Effects
of tamoxifen on insulin-like growth factors, IGF binding pro-
teins and IGFBP-3 proteolysis in breast cancer patients.  Anti-
cancer Res 2003, 23:2815-2820.
6. Laban C, Bustin SA, Jenkins PJ: The GH-IGF-I axis and breast can-
cer.  Trends Endocrinol Metab 2003, 14:28-34.
7. Furstenberger G, Senn E, Morant R, Bolliger B, Senn HJ: Serum lev-
els of IGF-1 and IGFBP-3 during adjuvant chemotherapy for
primary breast cancer.  Breast 2006, 15:64-68.
8. Rollison DE, Newschaffer CJ, Tao Y, Pollak M, Helzlsouer KJ: Pre-
menopausal levels of circulating insulin-like growth factor I
and the risk of postmenopausal breast cancer.  Int J Cancer
2006, 118:1279-1284.
9. Grimberg A, Cohen P: Role of insulin-like growth factors and
their binding proteins in growth control and carcinogenesis.
J Cell Physiol 2000, 183:1-9.
10. Duschek EJ, Gooren LJ, Netelenbos C: Comparison of effects of
the rise in serum testosterone by raloxifene and oral testo-
sterone on serum insulin-like growth factor-1 and insulin-like
growth factor binding protein-3.  Maturitas 2005, 51:286-293.
11. Mantzoros CS, Tzonou A, Signorello LB, Stampfer M, Trichopoulos
D, Adami HO: Insulin-like growth factor 1 in relation to pros-
tate cancer and benign prostatic hyperplasia.  Br J Cancer 1997,
76:1115-1118.
12. Yu H, Spitz MR, Mistry J, Gu J, Hong WK, Wu X: Plasma levels of
insulin-like growth factor-I and lung cancer risk: a case-con-
trol analysis.  J Natl Cancer Inst 1999, 91:151-156.
13. Hankinson SE, Willett WC, Colditz GA, Hunter DJ, Michaud DS,
Deroo B, Rosner B, Speizer FE, Pollak M: Circulating concentra-
tions of insulin-like growth factor-I and risk of breast cancer.
Lancet 1998, 351:1393-1396.
14. Toniolo P, Bruning PF, Akhmedkhanov A, Bronfer JM, Koenig KL,
Lukanova A, Shore RE, Zeleniuch-Jacquotte A: Serum insulin-like
growth factor-I and breast cancer.  Int J Cancer 2000,
88:828-832.
15. Vignon F, Bouton MM, Rochefort H: Antiestrogens inhibit the
mitogenic effect of growth factors on breast cancer cells in
the total absence of estrogens.  Biochem Biophys Res Commun
1987, 146:1502-1508.
16. Fisher B, Constantino JP, Wickerham DL, Redmon CK, Kavanah M,
Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, Daly M,
Wieand S, Tan-Chiu E, Ford L, Wolmark N: Tamoxifen for pre-
vention of breast cancer: report of the National Surgical
Adjuvant Breast and Bowel Project P-1 Study.  J Natl Cancer
Inst 1998, 90:1371-1388.
17. da Silva BB, Lopes IM, Gebrim LH: Effects of raloxifene on normal
breast tissue from premenopausal women.  Breast Cancer Res
Treat 2006, 95:99-103.
18. Delmas PD, Bjarnason NH, Mitlak BH, Ravoux AC, Shah AS, Huster
WJ, Draper M, Christiansen C: Effects of raloxifene on bone min-
eral density, serum cholesterol concentrations, and uterine
endometrium in postmenopausal women.  N Engl J Med 1997,
337:1641-1647.
19. Cummings SR, Eckert S, Krueger KA, Grady D, Powels TJ, Cauley JA,
Norton L, Nickelsen T, Bjarnason NH, Morrow M, Lippman ME, Black
D, Glusman JE, Costa A, Jordan VC: The effect of raloxifene on
risk of breast cancer in postmenopausal women: results
from the MORE randomized trial. Multiple Outcomes of
Raloxifene Evaluation.  JAMA 1999, 281:2189-2197.
20. Vogel VG, Constantino JP, Wickerham DL, Cronin WM, Cecchini RS,
Atkins JN, Bevers TB, Fehrenbacher L, Pajon  Jr, Wade JL 3rd, Rabi-
doux A, Margolese RG, James J, Lippman SM, Runowicz CD, Ganz PA,
Reis SE, McCaskill-Stevens W, Ford LG, Jordan VC, Wolmark N:
Effects of tamoxifen vs raloxifene on the risk of developing
invasive breast cancer and other disease outcomes: the
NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial.
JAMA 2006, 295:2727-2741.
21. Fisher B, Powles TJ, Pritchard KJ: Tamoxifen for the prevention
of breast cancer.  Eur J Cancer 2000, 36:142-150.
22. Gagliardi A, Collins DC: Inhibition of angiogenesis by antiestro-
gens.  Cancer Res 1993, 53:533-535.
23. da Silva BB, da Silva RG Junior, Borges US, da Silveira Filho MA, Pimen-
tel IC, Gebrim LH, Simões Mde J, Baracat EC: Quantification of
angiogenesis induced in rabbit cornea by breast carcinoma
of women treated with tamoxifen.  J Surg Oncol 2005, 90:77-80.
24. Blackwell KL, Haroon ZA, Shan S, Saito W, Broadwater G, Greenberg
CS, Dewhirst MW: Tamoxifen inhibits angiogenesis in estro-
gen receptor-negative animal models.  Clin Cancer Res 2000,
6(11):4359-4364.Page 4 of 4
(page number not for citation purposes)


Evaluation of insulin-like growth factor-I in postmenopausal women with breast cancer treated with raloxifene

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Evaluation of insulin-like growth factor-I in postmenopausal women with breast cancer treated with raloxifene

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