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AS290 - Cadmium Exposure and Risk of Breast Cancer in the WHI
Investigator Names and Contact Information
Polly Newcomb, Ph.D. [pnewcomb@fhcrc.org]
Introduction/Intent
Most of the established risk factors for breast cancer are believed to act through changes in endogenous or exogenous hormone levels. Cadmium is a widespread heavy metal environmental pollutant resulting from industrial and agricultural practices, which accumulates in the body over a lifetime. In vitro experiments show that cadmium may have estrogenic properties. Therefore, we hypothesize that cadmium body burden is a risk factor for breast cancer. We have previously found an association between high cadmium body burden, assessed by measurement of urinary cadmium, and risk of breast cancer in a pilot, cross-sectional case-control study. We now plan to test further test our hypothesis within the Women’s Health Initiative (WHI) study. The ~11,000 participants in the WHI Bone Density sub-study donated urine prospectively at enrollment in the study. We plan to conduct a case-cohort study to assay these urine samples for cadmium burden, and combined with questionnaire data, examine the association between urinary cadmium level and incidence of breast cancer.
Aims
Known risk factors for breast cancer account for only a modest fraction of the population attributable risk.1-3 The search for new risk factors must continue, and one consideration should be new or neglected environmental exposures. Although epidemiologic studies of pesticides have been unsuccessful in identifying associations with breast cancer risk,4 exposure to heavy metals is a promising research focus. In vitro and in vivo data demonstrate the carcinogenic effects of cadmium, a toxic, bioaccumulating heavy metal that is ubiquitously increasing in the environment.5, 6 Women have substantially higher levels of cadmium than men because of differences in gut metabolism, thus potentially placing them at greater carcinogenic risk.7 In our own pilot case-control study, we have demonstrated an increase in breast cancer risk associated with higher urinary levels of cadmium.8 Such a relationship is plausible, because cadmium is a known carcinogen, and may be an estrogen mimic,9-12 disrupt reproduction,13 and increase estrogen-receptor mediated proliferation.14-16 There are, however, only very limited data that have evaluated cadmium in relation to the most common cancer in United States women. We propose a case-cohort study with the Women’s Health Initiative (WHI) cohort to examine the following aim:
Specific Aim: Evaluate the relation between urinary cadmium, defined in quartiles of creatinine-corrected concentration, and invasive breast cancer risk.
Hypothesis: Breast cancer risk is higher in women with elevated levels of cadmium.
In addition, to maximize the information obtained from these samples and to generate hypotheses for future studies, we plan to explore several secondary aims using the data produced by these assays. First, we will investigate possible interactions between cadmium and established risk factors for invasive breast cancer, such as use of hormone replacement therapy, parity, and elevated body mass index. Second, we will examine whether the association between cadmium concentration and risk of breast cancer differs between sub-types of breast cancer, defined by expression of estrogen receptors (ER), or progesterone receptors (PR); or by histology (lobular, non-lobular). Finally, we will explore the association between heavy metals other than cadmium and risk of breast cancer.
To accomplish this, we will conduct a case-cohort study among participants in the Women’s Health Initiative at clinical sites in Birmingham, Tucson, and Pittsburgh. At these three sites, urine was collected at baseline, 3 years, and 6 years from approximately 10,800 women as part of the Bone Density sub-study (BD). In urine collected at enrollment in WHI, a panel of heavy metals, including cadmium, will be assayed at the Wisconsin State Hygiene Laboratory (WSHL) for all breast cancer cases identified by July 1, 2010 (as of August 2009, 481 cases) and a random sample of 7% (756) of BD participants. These new data will be combined with WHI questionnaire data on dietary habits, reproductive history, tobacco use, and pathology reports to address our primary hypothesis.
References
1. Madigan MP, Troisi R, Potischman N, Dorgan JF, Brinton LA, Hoover RN. Serum hormone levels in relation to reproductive and lifestyle factors in postmenopausal women (United States). Cancer Causes Control. Mar 1998;9(2):199-207.
2. Vogel VG, Taioli E. Have we found the ultimate risk factor for breast cancer? J Clin Oncol. Apr 20 2006;24(12):1791-1794.
3. Sprague BL, Trentham-Dietz A, Egan KM, Titus-Ernstoff L, Hampton JM, Newcomb PA. Proportion of invasive breast cancer attributable to risk factors modifiable after menopause. Am J Epidemiol. Aug 15 2008;168(4):404-411.
4. Safe S. Clinical correlates of environmental endocrine disruptors. Trends Endocrinol Metab. May-Jun 2005;16(4):139-144.
5. Nordberg GF, Herber RFM, Alessio L, eds. Cadmium in the human environment: toxicity and carcinogenesis. Lyon: International Agency for Research on Cancer; 1992. IARC Scientific Publication # 118.
6. Huff J, Lunn RM, Waalkes MP, Tomatis L, Infante PF. Cadmium-induced cancers in animals and in humans. Int J Occup Environ Health. Apr-Jun 2007;13(2):202-212.
7. Vahter M, Akesson A, Liden C, Ceccatelli S, Berglund M. Gender differences in the disposition and toxicity of metals. Environ Res. May 2007;104(1):85-95.
8. McElroy JA, Shafer MM, Trentham-Dietz A, Hampton JM, Newcomb PA. Cadmium exposure and breast cancer risk. J Natl Cancer Inst. Jun 21 2006;98(12):869-873.
9. Choe SY, Kim SJ, Kim HG, et al. Evaluation of estrogenicity of major heavy metals. Sci Total Environ. Aug 1 2003;312(1-3):15-21.
10. McMurray CT, Tainer JA. Cancer, cadmium and genome integrity. Nat Genet. Jul 2003;34(3):239-241.
11. Johnson MD, Kenney N, Stoica A, et al. Cadmium mimics the in vivo effects of estrogen in the uterus and mammary gland. Nat Med. Aug 2003;9(8):1081-1084.
12. Safe S. Cadmium's disguise dupes the estrogen receptor. Nat Med. Aug 2003;9(8):1000-1001.
13. Henson MC, Chedrese PJ. Endocrine disruption by cadmium, a common environmental toxicant with paradoxical effects on reproduction. Exp Biol Med (Maywood). May 2004;229(5):383-392.
14. Brama M, Gnessi L, Basciani S, et al. Cadmium induces mitogenic signaling in breast cancer cell by an ERalpha-dependent mechanism. Mol Cell Endocrinol. Jan 29 2007;264(1-2):102-108.
15. Stoica A, Katzenellenbogen BS, Martin MB. Activation of estrogen receptor-alpha by the heavy metal cadmium. Mol Endocrinol. Apr 2000;14(4):545-553.
16. Garcia-Morales P, Saceda M, Kenney N, et al. Effect of cadmium on estrogen receptor levels and estrogen-induced responses in human breast cancer cells. J Biol Chem. Jun 17 1994;269(24):16896-16901.