CORRESPONDENCE

Re: Are Breast Density and Bone Mineral Density Independent Risk Factors for Breast Cancer?

Jennifer A. Harvey

Correspondence to: Jennifer A. Harvey, MD, Box 800170, Department of Radiology, University of Virginia, Charlottesville, VA 22908 (e-mail: jah7w{at}virginia.edu).

I read with interest the article by Kerlikowske et al. (1) demonstrating that breast density is strongly associated with increased breast cancer risk, whereas bone mineral density (BMD) is not. Both breast density and BMD should, at least in part, reflect exposure to estrogen. The association of breast cancer risk with one but not the other is therefore surprising. The authors speculate that "a component of breast density that is independent of estrogen-mediated effects may contribute to breast cancer risk."

Alternatively, the lack of parallel influences of breast density and BMD on breast cancer risk may reflect differences in tissue-specific estrogen activity. Polymorphisms in genes that control estrogen production (i.e., CYP1A1, CYP17, and CYP19) or metabolism (i.e., COMT) could account for population differences in estrogen exposure (2). Aromatase (encoded by CYP19) is the rate-limiting step in the production of estrogen by converting C19 androgens to C18 estrogens (e.g., androstenedione to estrone and testosterone to estradiol). Aromatase excess syndrome is rare in humans and is associated with macromastia and higher-than-average BMD (3), whereas aromatase-deficient mice have underdeveloped breasts and osteopenia (4). Studies of various polymorphisms of the CYP19 gene have not shown a consistent association with breast cancer risk (5).

The CYP19 gene has a large promoter region that contains 10 tissue-specific promoters that are active in brain, placenta, bone, and breast; the translated protein is the same in all tissues (6). Each promoter is regulated by distinct hormones or cytokines (6). The strong association between breast density and breast cancer risk reported by Kerlikowske et al. may be due to polymorphisms in tissue-specific promoter regions that regulate aromatase production in the breast without affecting aromatase production in bone or other tissues. Polymorphisms in other genes that regulate estrogen production or breakdown may also result in different tissue-specific estrogen levels. No strong relationships have, as yet, been identified among steroid hormone pathway genes and mammographic breast density (7), and polymorphisms in the promoter region of CYP19 have not yet been identified. Evaluation of polymorphisms in steroid hormone pathway genes may eventually identify common low-penetrance genes that may ultimately explain many cases of sporadic breast cancer.

NOTES

Editor's note: Kerlikowske et al. declined an invitation to respond to this correspondence.

REFERENCES

(1) Kerlikowske K, Shepherd J, Creasman J, Tice JA, Ziv E, Cummings SR. Are breast density and bone mineral density independent risk factors for breast cancer? J Natl Cancer Inst 2005;97:368–74.[Abstract/Free Full Text]

(2) Thompson PA, Ambrosone C. Molecular epidemiology of genetic polymorphisms in estrogen metabolizing enzymes in human breast cancer. J Natl Cancer Inst Monogr 2000;27:125–34.[Medline]

(3) Martin RM, Lin CJ, Nishi MY, Billerbeck AE, Latronico AC, Russell DW, et al. Familial hyperestrogenism in both sexes: clinical, hormonal, and molecular studies of two siblings. J Clin Endocrinol Metab 2003;88:3027–34.[Abstract/Free Full Text]

(4) Fisher CR, Graves KH, Parlow AF, Simpson ER. Characterization of mice deficient in aromatase (ArKO) because of targeted disruption of the cyp19 gene. Proc Natl Acad Sci U S A 1998;95:6965–70.[Abstract/Free Full Text]

(5) Haiman CA, Hankinson SE, Spiegelman D, DeVivo I, Colditz GA, Willett WC, et al. A tetranucleotide repeat polymorphism in CYP19 and breast cancer risk. Int J Cancer 2000;87:204–10.[CrossRef][ISI][Medline]

(6) Bulun SE, Sebastian S, Takayama K, Suzuki T, Sasano H, Shozu M. The human CYP19 (aromatase P450) gene: update on physiologic roles and genomic organization of promoters. J Steroid Biochem Mol Biol 2003;86:219–24.[CrossRef][ISI][Medline]

(7) Haiman CA, Hankinson SE, DeVivo I, Guillemette C, Ishibe N, Hunter DJ, et al. Polymorphisms in steroid hormone pathways genes and mammographic density. Breast Cancer Res Treat 2003;77:27–36.[CrossRef][ISI][Medline]



             
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