Journal of the National Cancer Institute Advance Access originally published online on March 11, 2008
JNCI Journal of the National Cancer Institute 2008 100(6):443-444; doi:10.1093/jnci/djn016
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© The Author 2008. Published by Oxford University Press.
CORRESPONDENCE |
Re: C-Reactive Protein and Risk of Breast Cancer
Affiliations of authors: Departments of Environmental Medicine (AZJ, YG, KLK, AAA, PT, RES) and Obstetrics and Gynecology (AAA, PT), New York University School of Medicine, New York (AZJ, YG, KLK, AAA, PT, RES); New York University Cancer Institute, New York (AZJ, KLK, AAA, PT); Netherlands Cancer Institute/Antoni van Leeuwenhoekhuis, Amsterdam, The Netherlands (PFB, JMGB); Radiation Effects Research Foundation, Hiroshima, Japan (RES)
Correspondence to: Anne Zeleniuch-Jacquotte, MD, MS, Department of Environmental Medicine, New York University School of Medicine, 650 1st Ave, Rm 539, New York 10016 (e-mail: anne.jacquotte{at}med.nyu.edu).
Zhang et al. (1) reported no association between plasma levels of C-reactive protein (CRP) in apparently healthy women 45 years of age and older and subsequent breast cancer risk. The large study size (892 patients among 27919 participants in the Women's Health Study) argues against lack of power as an explanation for this lack of association.
To minimize a potential influence of prediagnostic tumors on CRP levels, analyses excluding patients who were diagnosed within the first 2 and 5 years of follow-up were conducted, which also showed null results. However, it also would be of interest to see the association between CRP and breast cancers diagnosed within 2 or 5 years of blood collection. The microenvironment of a substantial proportion of breast cancers is characterized by diffuse, low-degree inflammation, with immune cells present (2). Cytokines and other mediators produced by these cells are known to promote tumor growth. Some of these cytokines, especially interleukin-6 (IL-6), are known to stimulate hepatic release of CRP (3). An association of circulating CRP with breast cancer occurring fairly shortly after blood donation would provide evidence of inflammatory involvement in prediagnostic breast cancer. We observed such an association (Table 1) in the New York University Women's Health Study, a prospective cohort of 14274 women (4). The Behring NA latex test (5) was used to measure serum CRP in 85 postmenopausal women with breast cancers who were diagnosed 6 months to 5.5 years after blood donation and two age-matched control subjects per case subject. Because of the short intervals between blood donation and cancer diagnosis, tumors are likely to have been present at the time of blood donation in most cases.
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One of the only two interactions observed by Zhang et al. (1) was with body mass index (BMI). Because BMI is positively associated with breast cancer risk only in postmenopausal women, it would be of interest to see the effect of BMI on the CRP–breast cancer association by stratifying by menopausal status. In our study, which was limited to women who were postmenopausal at both blood donation and diagnosis, we observed strong correlations of CRP with BMI and circulating total and sex hormone–binding globulin–bound estradiol (Spearman correlation coefficient, r = 0.46, r = 0.34, and r = –0.53, respectively), and the CRP–breast cancer association was attenuated after adjusting for either BMI or estradiol (Table 1). One interpretation is that BMI and estradiol confound the CRP–breast cancer association. But because IL-6 may stimulate estrogen synthesis in peripheral tissues (6), another possible interpretation is that IL-6 and endogenous estrogens contribute to the development of breast cancer in postmenopausal women through a common pathway. Namely, women with more adipose tissue produce more IL-6 than lean women (7) and elevated IL-6 leads to both increased hepatic production of CRP and increased aromatization of androgens to estrogens in peripheral tissues.
Prospective epidemiologic studies with measurement of cytokines thought to affect tumor growth would be of interest. In these studies, it would be important to consider lag time between blood donation and diagnosis, menopausal status, and the relationships between BMI, cytokines, and levels of circulating estrogens.
REFERENCES
1. Zhang SM, Lin J, Cook NR, et al. C-reactive protein and risk of breast cancer. J Natl Cancer Inst (2007) 99(11):890–894.
2. Lee AH, Gillett CE, Ryder K, Fentiman IS, Miles DW, Millis RR. Different patterns of inflammation and prognosis in invasive carcinoma of the breast. Histopathology (2006) 48(6):692–701.[CrossRef][Web of Science][Medline]
3. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med (1999) 340(6):448–454.
4. Zeleniuch-Jacquotte A, Shore RE, Koenig KL, et al. Postmenopausal levels of estrogen, androgen, and SHBG and breast cancer risk: long-term results of a prospective study. Br J Cancer (2004) 90(1):153–159.[CrossRef][Web of Science][Medline]
5. Erlandsen EJ, Randers E. Reference interval for serum C-reactive protein in healthy blood donors using the Dade Behring N Latex CRP mono assay. Scand J Clin Lab Invest (2000) 60(1):37–43.[CrossRef][Web of Science][Medline]
6. Purohit A, Ghilchik MW, Leese MP, Potter BV, Reed MJ. Regulation of aromatase activity by cytokines, PGE2 and 2-methoxyoestrone-3-O-sulphamate in fibroblasts derived from normal and malignant breast tissues. J Steroid Biochem Mol Biol (2005) 94(1–3):167–172.[CrossRef][Web of Science][Medline]
7. Piche ME, Lemieux S, Weisnagel SJ, Corneau L, Nadeau A, Bergeron J. Relation of high-sensitivity C-reactive protein, interleukin-6, tumor necrosis factor-alpha, and fibrinogen to abdominal adipose tissue, blood pressure, and cholesterol and triglyceride levels in healthy postmenopausal women. Am J Cardiol (2005) 96(1):92–97.[CrossRef][Web of Science][Medline]
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Del.icio.us What's this?
J Natl Cancer Inst 2007 99: 890-894.
J Natl Cancer Inst 2008 100: 444-445.
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