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Breast Cancer and Prenatal Alcohol Exposure

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Breast Cancer and Prenatal Alcohol Exposure

  1. 1. © 2001 Medical Council on Alcoholism 276 Since the pioneering work of Hiatt and Bawol (1984), there has amassed a considerable amount of evidence that moderate-to-heavy alcohol consumption increases risk of breast cancer in women (Willett et al., 1987; Longnecker, 1999). A plausible mechanism is by alcohol’s effects on circulating hormone levels. Alcohol administration has been reported to increase circulating oestradiol levels in pre-menopausal women (Reichman et al., 1993); the evidence is mixed in post- menopausal women (Purohit, 1998). In a cross-sectional study of pre-menopausal women, Muti et al. (1998) determined an association between reported alcohol consumption and serum oestradiol levels during the luteal phase of the menstrual cycle, and found an 18% elevation in drinkers, consuming an average 1 drink per day, compared to abstainers. It is not clear how alcohol affects circulating oestradiol levels. Alcohol has been reported to increase aromatase activity; i.e., the conversion of testosterone to oestrogens, resulting in reduced testosterone and increased oestrogen levels (Gavaler and Van Thiel, 1992). Alcohol also might interact with luteinizing hormone produc- tion from the pituitary (Rettori and McCann, 1997), resulting in increased oestradiol release from the ovaries. In addition to affecting oestrogen levels, alcohol appears to influence melatonin. Alcohol administration has been reported to reduce the nocturnal rise in serum melatonin in rats (Moss et al., 1986), and in humans (Ekman et al., 1993; Rojmark et al., 1993) under experimental conditions. In a large cross- sectional study, Stevens et al. (2000) found a significant inverse association of alcohol consumption and urinary 6-sulphatoxymelatonin, a good indicator of nocturnal blood levels (Cook et al., 2000), in healthy women living under nor- mal conditions in the Seattle area. Importantly, there was no effect of one drink on melatonin level, but a 9% reduction with 2 drinks, 15% with 3 drinks, and 17% with 4 drinks or more. It may be that an increase in circulating oestradiol levels and a reduction in melatonin levels after alcohol exposure, are not just simultaneous events, but causally related. Stevens and Hiatt (1987) suggested that alcohol ingestion may result in lowered melatonin levels which, in turn, may lead to elevated circulating oestradiol concentration in blood (Cohen et al., 1978). Specifically, decreased concentrations of melatonin might increase release of gonadotrophins, leading to an increase in ovarian oestrogen production (Kauppila et al., 1987; Penny et al., 1987; Voordouw et al., 1992; Brzezinski, 1997). Both high oestrogen levels and low melatonin levels have been implicated in increasing the risk to develop breast cancer. Findings in human breast cancer cells growing in culture and in animal models (Clarke et al., 1992), as well as in epidemiological studies, at least in post-menopausal women (Key, 1999; Kabuto et al., 2000), link elevated circulating oestrogen levels to increased breast cancer risk. In addition, in vivo data indicate that reduced melatonin levels can increase chemically induced mammary cancer in rats (Tamarkin et al., 1981; Blask et al., 1991). The epidemiology is, however, quite sparse (Tamarkin et al., 1982) due in part to the fact that there has not, until recently, been a reliable technique for estimating nocturnal circulating melatonin levels that is feasible to use in large-scale epidemiological studies. These observations can be considered in the context of the hypothesis that an elevated exposure to oestrogens in utero will increase the lifetime risk of breast cancer (Trichopoulos, 1990) by altering normal breast development. This hypothesis was subsequently supported in a number of epidemiological studies (Potischman and Troisi, 1999). Animal models also support the hypothesis and show that elevated in utero oestradiol levels lead to altered mammary gland develop- ment (Hilakivi-Clarke et al., 1997); further, an exposure of pregnant rats to oestradiol, or feeding them a diet high in n-6 polyunsaturated fatty acid (PUFA), which significantly raises circulating oestradiol levels, results in increased 7,12-dimethylbenz[a]anthracene-induced mammary tumour incidence in their female offspring. For women who are pregnant, ingestion of alcohol, even in moderation, may lead to elevated circulating oestradiol levels, either through a reduction of melatonin or some other mechan- ism. This may then affect the developing mammary tissue such that the lifetime risk of breast cancer is raised in their daughters. REFERENCES Blask, D. E., Pelletier, D. B., Hill, S. M., Lemus-Wilson, A., Grosso, D. S., Wilson, S. T. and Wise, M. E. (1991) Pineal melatonin inhibition of tumor promotion in the N-nitroso-N-methylurea model of mammary carcinogenesis: potential involvement of antiestrogenic mechanisms in vivo. Journal of Cancer Research and Clinical Oncology 117, 526–532. Brzezinski, A. (1997) Melatonin in humans. New England Journal of Medicine 336, 186–195. Alcohol & Alcoholism Vol. 36, No. 3, pp. 276–277, 2001 LETTER TO THE EDITORS ALCOHOL EXPOSURE IN UTERO AND BREAST CANCER RISK LATER IN LIFE RICHARD G. STEVENS* and LEENA HILAKIVI-CLARKE1 University of Connecticut Health Center, Farmington, CT 06030 and 1 Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA (Received 24 October 2000; accepted 4 January 2001) *Author to whom correspondence should be addressed.
  2. 2. LETTER TO THE EDITORS 277 Clarke, R., Dickson, R. B. and Lippman, M. E. (1992) Hormonal aspects of breast cancer. Growth factors, drugs and stromal interactions. Critical Reviews in Oncology/Hematology 12, 1–23. Cohen, M., Lippman, M. and Chabner, B. (1978) Role of pineal gland in aetiology and treatment of breast cancer. Lancet ii, 814–816. Cook, M., Graham, C., Kavet, R., Stevens, R. G., Davis, S. and Kheifets, L. (2000) Urinary assessment of pineal melatonin production in women. Journal of Pineal Research 28, 41–47. Ekman, A. C., Leppäluoto, J., Huttunen, P., Aranko, K. and Vakkuri, O. (1993) Ethanol inhibits melatonin secretion in healthy volunteers in a dose-dependent randomized double blind cross-over study. Journal of Clinical Endocrinology and Metabolism 77, 780–783. Gavaler, J. S. and Van Thiel, D. H. (1992) The association between moderate alcoholic beverage consumption and serum estradiol and testosterone levels in normal postmenopausal women: relationship to the literature. Alcoholism: Clinical and Experimental Research 16, 87–92. Hiatt, R. A. and Bawol, R. D. (1984) Alcoholic beverage consumption and breast cancer. American Journal of Epidemiology 120, 676–683. Hilakivi-Clarke, L., Clarke, R., Onojafe, I., Raygada, M., Cho, E. and Lippman, M. (1997) A maternal diet high in n-6 polyunsaturated fats alters mammary gland development, puberty onset, and breast cancer risk among female rat offspring. Proceedings of the National Academy of Sciences of the USA 94, 9372–9377. Kabuto, M., Akiba, S., Stevens, R. G., Neriishi, K. and Land, C. E. (2000) A prospective study of estradiol and breast cancer in Japanese women. Cancer Epidemiology and Biomarkers Preview 9, 575–579. Kauppila, A., Kilevä, A., Pakarinen, A. and Vakkuri, O. (1987) Inverse seasonal relationship between melatonin and ovarian activity in humans in a region with a strong seasonal contrast in luminosity. Journal of Clinical Endocrinology and Metabolism 65, 823–828. Key, T. J. (1999) Serum oestradiol and breast cancer risk. Endocrine- Related Cancer 6, 175–180. Longnecker, M. P. (1999) The Framingham results on alcohol and breast cancer. American Journal of Epidemiology 149, 102–104. Moss, H. B., Tamarkin, L., Majchrowicz, E., Martin, P. R. and Linnoila, M. (1986) Pineal function during ethanol intoxication, dependence, and withdrawal. Life Sciences 39, 2209–2214. Muti, P., Trevisan, M., Micheli, A., Krogh, V., Bolelli, G., Sciajno, R. et al. (1998) Alcohol consumption and total estradiol in pre- menopausal women. Cancer Epidemiology and Biomarkers Preview 7, 189–193. Penny, R., Stanczyk, F. and Goebelsmann, U. (1987) Melatonin: data consistent with a role in controlling ovarian function. Journal of Endocrinological Investigations 10, 499–505. Potischman, N. and Troisi, R. (1999) In utero and early life exposures in relation to risk of breast cancer. Cancer Causes and Control 10, 561–573. Purohit, V. (1998) Moderate alcohol consumption and estrogen levels in postmenopausal women: a review. Alcoholism: Clinical and Experimental Research 22, 994–997. Reichman, M. E., Judd, J. T., Longcope, C., Schatzkin, A., Clevidence, B. A., Nair, P. P., Campbell, W. S. and Taylor, P. R. (1993) Effects of alcohol consumption on plasma and urinary hormone concentrations in premenopausal women. Journal of the National Cancer Institute 85, 722–727. Rettori, V. and McCann, S. M. (1997) The mechanism of action of alcohol to suppress gonadotrophin secretion. Molecular Psychiatry 2, 350–354. Rojmark, S., Wikner, J., Adner, N., Andersson, D. E. and Wetterberg, L. (1993) Inhibition of melatonin secretion by ethanol in man. Metabolism 42, 1047–1051. Stevens, R. G. and Hiatt, R. A. (1987) Alcohol, melatonin, and breast cancer. New England Journal of Medicine 317, 1287. Stevens, R. G., Davis, S., Mirick, D. K., Kheifets, L. and Kaune, W. (2000) Alcohol consumption and urinary concentration of 6-sulphatoxymelatonin in healthy women. Epidemiology 11, 660–665. Tamarkin, L., Cohen, M., Roselle, D., Reichert, C., Lippman, M. and Chabner, B. (1981) Melatonin inhibition and pinealectomy enhancement of 7,12-dimethylbenz(a)anthracene-induced mammary tumors in the rat. Cancer Research 41, 4432–4436. Tamarkin, L., Danforth, D. and Lichter, A. (1982) Decreased nocturnal plasma melatonin peak in patients with estrogen receptor positive breast cancer. Science 216, 1003–1005. Trichopoulos, D. (1990) Hypothesis: does breast cancer originate in utero? Lancet 335, 939–940. Voordouw, G., Euser, R., Verdonk, R. E., Alberda, B. T., de Jong, F. H., Drogendijk, A. C. et al. (1992) Melatonin and melatonin–progestin combinations alter pituitary–ovarian function in women and can in- hibit ovulation. Journal of Clinical Endocrinology and Metabolism 74, 108–117. Willett, W. C., Stampfer, M. J., Colditz, G. A., Rosner, B. A., Hennekens, C. H. and Speizer, F. E. (1987) Moderate alcohol consumption and the risk of breast cancer. New England Journal of Medicine 316, 1174–1180.

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