Journal of the National Cancer Institute Advance Access originally published online on October 9, 2009
JNCI Journal of the National Cancer Institute 2009 101(21):1501-1509; doi:10.1093/jnci/djp331
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ARTICLES |
Prospective Case–Control Study of Serum Müllerian Inhibiting Substance and Breast Cancer Risk
Affiliations of authors: Fox Chase Cancer Center, Philadelphia, PA (JFD, BLE, CMS, CSS, AKG); Department of Obstetrics and Gynecology and Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA (FZS); Information Management Services, Rockville, MD (LLK); Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD (LAB)
Correspondence to: Joanne F. Dorgan, PhD, MPH, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA 19111 (e-mail: joanne.dorgan{at}fccc.edu).
Background: Müllerian inhibiting substance (MIS) is a member of the transforming growth factor β family of growth and differentiation factors that inhibits elongation and branching of mammary ducts and has been shown to inhibit mammary tumor growth in vitro and in animal models. The objective of this study was to determine whether serum MIS levels are associated with breast cancer risk.
Methods: We conducted a prospective case–control study of 309 participants who were registered in the Columbia, Missouri Serum Bank. Each of 105 in situ or invasive breast cancer case patients with prediagnostic serum collected before menopause was matched to two control subjects by age, date, menstrual cycle day, and time of day of blood collection. MIS was measured in serum by using an enzyme-linked immunosorbent assay, and estradiol and testosterone concentrations were quantified by using specific radioimmunoassays. Data were analyzed using conditional logistic regression. All tests of statistical significance were two-sided.
Results: The relative odds ratio of breast cancer for women in increasing MIS quartiles were 1, 2.8 (95% confidence interval [CI] = 1.0 to 7.4), 5.9 (95% CI = 2.4 to 14.6), and 9.8 (95% CI = 3.3 to 28.9, Ptrend < .001). The association of MIS with breast cancer was weaker in women who were not taking oral contraceptives at the time of blood collection, but adjustment for estradiol and testosterone levels did not materially alter results for these women. The association of MIS with breast cancer did not vary by age at blood collection but was stronger among women who were diagnosed with breast cancer at an older age than among those who were diagnosed at a younger age.
Conclusion: MIS may be a novel biomarker of increased breast cancer risk. Additional research including confirmatory epidemiological studies and mechanistic studies is needed.
| CONTEXT AND CAVEATS Prior knowledge Müllerian inhibiting substance (MIS) inhibits mammary tumor growth in vitro and in mouse models of breast cancer. Study design Prospective case–control study to determine whether MIS serum concentrations from blood samples that were collected before diagnosis are associated with breast cancer risk. Contributions Increasing MIS serum concentrations were associated with increased breast cancer risk in this population. Adjustment for estrogen and testosterone levels did not change the results. The association did not vary with age at blood collection but was stronger among women who were diagnosed with breast cancer at an older age. Implications Increased serum concentrations of MIS may be associated with increased breast cancer risk. Limitations The association of increased serum MIS concentrations and increased risk of breast cancer is in contrast to previous findings in vitro and in animal models and what is known about the mechanisms of MIS on breast physiology. The patients in the population less frequently used oral contraceptives than the control subjects, which contrasts with previous data, and could indicate that the control population was not representative of the general population. From the Editors
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Manuscript received January 10, 2009; revised July 31, 2009; accepted August 24, 2009.
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J Natl Cancer Inst 2009 101: 1435.