iBreast cancer research and treatment, Vol. 109, No. 1. (May 2008), pp. 123-139./ibr /br /Risk factors for the newly identified "intrinsic" breast cancer subtypes (luminal A, luminal B, basal-like and human epidermal growth factor receptor 2-positive/estrogen receptor-negative) were determined in the Carolina Breast Cancer Study, a population-based, case-control study of African-American and white women. Immunohistochemical markers were used to subtype 1,424 cases of invasive and in situ breast cancer, and case subtypes were compared to 2,022 controls. Luminal A, the most common subtype, exhibited risk factors typically reported for breast cancer in previous studies, including inverse associations for increased parity and younger age at first full-term pregnancy. Basal-like cases exhibited several associations that were opposite to those observed for luminal A, including increased risk for parity and younger age at first term full-term pregnancy. Longer duration breastfeeding, increasing number of children breastfed, and increasing number of months breastfeeding per child were each associated with reduced risk of basal-like breast cancer, but not luminal A. Women with multiple live births who did not breastfeed and women who used medications to suppress lactation were at increased risk of basal-like, but not luminal A, breast cancer. Elevated waist-hip ratio was associated with increased risk of luminal A in postmenopausal women, and increased risk of basal-like breast cancer in pre- and postmenopausal women. The prevalence of basal-like breast cancer was highest among premenopausal African-American women, who also showed the highest prevalence of basal-like risk factors. Among younger African-American women, we estimate that up to 68% of basal-like breast cancer could be prevented by promoting breastfeeding and reducing abdominal adiposity.br /iRC Millikan, B Newman, CK Tse, PG Moorman, K Conway, LV Smith, MH Labbok, J Geradts, JT Bensen, S Jackson, S Nyante, C Livasy, L Carey, HS Earp, CM Perou/i

iJournal of mammary gland biology and neoplasia, Vol. 7, No. 1. (January 2002), pp. 3-15./ibr /br /Ovarian and other hormones are major determinants of breast cancer risk. Particularly important is the accumulative exposure of the breast to circulating levels of the ovarian hormones estradiol and progesterone. A number of breast cancer risk factors can be understood in light of how they affect women's hormone profiles. Age is a marker for the onset and cessation of ovarian activity. Racial differences in hormone profiles correlate with breast cancer incidence patterns. Age at menarche not only serves as the chronological indicator of the onset of ovarian activity, but as a predictor of ovulatory frequency during adolescence and hormone levels in young adults, and has a long-lasting influence on risk. Age at menopause, another established breast cancer risk factor, marks the cessation of ovarian activity. Pregnancy history and lactation experience also are hormonal markers of breast cancer risk. Postmenopausal obesity, which is associated with higher levels of estrogen following cessation of ovarian activity, increases breast cancer risk, whereas physical activity, which can limit menstrual function, reduces risk. A relatively recent area of investigation is prenatal exposures like preeclampsia and low birth weight; both may be associated with lower in utero exposure to estrogen and also may predict lower breast cancer risk as an adult. Improved understanding of these exposures and their potential interactions with breast cancer susceptibility genes may, in the future, improve our prospects for breast cancer prevention.br /iL Bernstein/i

iClinical breast cancer, Vol. 8, No. 4. (August 2008), pp. 334-342./ibr /br /The perinatal period, childhood, and adolescence are important intervals for breast cancer risk development. Endogenous estrogen exposure is thought to be highest in utero, and exposure to estrogens throughout life plays an important role in increasing breast cancer risk. Some evidence suggests that breast tissue is not fully differentiated until after the first full-term pregnancy; thus, breast tissue might be more susceptible to carcinogenic influences during early life and adolescence. Birth characteristics of the daughter, including gestational age, birth weight, and birth length are associated with maternal hormone levels during the index pregnancy, and birth size has been related to daughter's timing of puberty and adult breast cancer incidence. Furthermore, early life and adolescence are critical times for maturation of the hypothalamic pituitary ovarian axis, which regulates production of ovarian hormones including estrogen and progesterone. Childhood height, growth, diet, and body mass index (BMI) have also been associated with breast cancer risk later in life. Of the examined characteristics, we conclude that the available evidence is suggestive of a positive relationship of breast cancer risk with birth weight, birth length, and adolescent height, and an inverse relationship with gestational age and childhood BMI, although several inconsistencies exist in the literature. The best evidence for a relationship of adolescent diet and adult breast cancer risk is indirect, and the relationship of diet, weight status, and weight gain in childhood deserves further attention. The interaction of birth characteristics with established risk factors over the life course, such as age at menarche, in addition to gene-environment interactions, require more research. Further study is also needed to clarify the biologic mechanisms influencing the observed associations.br /iEH Ruder, JF Dorgan, S Kranz, PM Kris-Etherton, TJ Hartman/i

iAdvances in experimental medicine and biology, Vol. 630 (2008), pp. 35-51./ibr /br /Cancer is one of the leading causes of human death and belongs to the group of main chronic noncommunicable diseases (NCD). Certain specific features ofNCD have raised the concept of 'normal' and 'successful' aging. The apparent paradox of simultaneous increase with aging of the diseases connected with estrogen deficiency as well as with estrogenic excess can be explained by the existence of the phenomenon of the switching of estrogen effects. An isolated or combined with the weakening of hormonal effect increase in genotoxic action of estrogens can modify the course ofage-associated pathology. In particular, such changes in estrogen effect may alter the biology of tumors to make them less favorable/more aggressive. Two other endocrine-genotoxic switchings (EGS) involving phenomena ofJanus (dual) function of glucose and adipogenotoxicosis may produce similar influences on tumor and other NCD biology. These three phenomena form a'basic triad' and can act independently of each other or in concert. EGS and their inductors may serve as targets for prevention and, probably, treatment of main noncommunicable diseases. The measures to correct components of the 'triad' can be divided into several groups aimed to optimally orchestrate the balance between endocrine and DNA-damagingeffects of estrogens, glucose and adipose tissue-related factors.br /iLM Berstein/i

iJournal of the National Cancer Institute, Vol. 95, No. 16. (20 August 2003), pp. 1218-1226./ibr /br /BACKGROUND: Obesity is associated with increased breast cancer risk among postmenopausal women. We examined whether this association could be explained by the relationship of body mass index (BMI) with serum sex hormone concentrations. METHODS: We analyzed individual data from eight prospective studies of postmenopausal women. Data on BMI and prediagnostic estradiol levels were available for 624 case subjects and 1669 control subjects; data on the other sex hormones were available for fewer subjects. The relative risks (RRs) with 95% confidence intervals (CIs) of breast cancer associated with increasing BMI were estimated by conditional logistic regression on case-control sets, matched within each study for age and recruitment date, and adjusted for parity. All statistical tests were two-sided. RESULTS: Breast cancer risk increased with increasing BMI (P(trend) =.002), and this increase in RR was substantially reduced by adjustment for serum estrogen concentrations. Adjusting for free estradiol reduced the RR for breast cancer associated with a 5 kg/m2 increase in BMI from 1.19 (95% CI = 1.05 to 1.34) to 1.02 (95% CI = 0.89 to 1.17). The increased risk was also substantially reduced after adjusting for other estrogens (total estradiol, non-sex hormone-binding globulin-bound estradiol, estrone, and estrone sulfate), and moderately reduced after adjusting for sex hormone-binding globulin, whereas adjustment for the androgens (androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone) had little effect on the excess risk. CONCLUSION: The results are compatible with the hypothesis that the increase in breast cancer risk with increasing BMI among postmenopausal women is largely the result of the associated increase in estrogens, particularly bioavailable estradiol.br /iTJ Key, PN Appleby, GK Reeves, A Roddam, JF Dorgan, C Longcope, FZ Stanczyk, HE Stephenson, RT Falk, R Miller, A Schatzkin, DS Allen, IS Fentiman, TJ Key, DY Wang, M Dowsett, HV Thomas, SE Hankinson, P Toniolo, A Akhmedkhanov, K Koenig, RE Shore, A Zeleniuch-Jacquotte, F Berrino, P Muti, A Micheli, V Krogh, S Sieri, V Pala, E Venturelli, G Secreto, E Barrett-Connor, GA Laughlin, M Kabuto, S Akiba, RG Stevens, K Neriishi, CE Land, JA Cauley, LH Kuller, SR Cummings, KJ Helzlsouer, AJ Alberg, TL Bush, GW Comstock, GB Gordon, SR Miller, C Longcope, /i

iCancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, Vol. 11, No. 10 Pt 1. (October 2002), pp. 953-971./ibr /br /Animal experiments and in vitro studies have shown that compounds found in tobacco smoke, such as polycyclic hydrocarbons, aromatic amines, and N-nitrosamines, may induce mammary tumors. The findings of smoking-specific DNA adducts and p53 gene mutations in the breast tissue of smokers also support the biological plausibility of a positive association between cigarette smoking and breast cancer, as does the detection of carcinogenic activity in breast fluid. However, epidemiological studies conducted over the past few decades have variably shown positive, inverse, or null associations. To help reconcile the discrepant findings, epidemiologists have paid increasing attention to measures of exposure to tobacco smoke that might be of the greatest etiological importance, to aspects of the smoker that might modify the association between smoking and breast cancer risk, and to the potentially different associations that might exist with different types of breast tumors, such as those with and without estrogen or progesterone receptors. Overall, the results of these studies suggest that smoking probably does not decrease the risk and indeed suggest that there may be an increased breast cancer risk with smoking of long duration, smoking before a first full-term pregnancy, and passive smoking. These findings require confirmation in future studies, as do suggestions of increased risk among women with certain genotypes.br /iPD Terry, TE Rohan/i

iThe Journal of clinical endocrinology and metabolism, Vol. 90, No. 3. (March 2005), pp. 1414-1419./ibr /br /Breast cancer risk increases with increased levels of alcohol consumption, potentially through an effect on sex hormone levels. In a cross-sectional study among Dutch participants (n = 17,357) of the European Prospective Investigation into Cancer and Nutrition conducted in Utrecht, The Netherlands (Prospect-EPIC), we investigated the relation between alcohol intake and estrogen and androgen levels. Alcohol intake was calculated from a food frequency questionnaire. Women were included if they were postmenopausal, had donated a blood sample, and did not use hormone replacement therapy or oral contraceptives at the time of blood donation (n = 1093). Women who consumed more than 25 g of alcohol per day had higher levels of estrone (P(trend) = 0.001), estradiol (P(trend) = 0.03), dehydroepiandrosterone sulfate (P(trend) = 0.18), and higher estrone/estradiol (P(trend) = 0.14) and estrone/androstenedione (P(trend) = 0.06) ratios, compared with nondrinkers. Levels of androstenedione, testosterone, and SHBG did not differ between women who consumed alcohol and nondrinkers. Furthermore, there were no differences in the free androgen index or estradiol to testosterone ratio. In conclusion, levels of estrogens and dehydroepiandrosterone sulfate are higher in women who consume more alcohol. This finding supports the hypothesis that alcohol use may increase breast cancer risk at least partially through an effect on sex steroid levels.br /iNC Onland-Moret, PH Peeters, YT van der Schouw, DE Grobbee, CH van Gils/i

iInternational journal of cancer. Journal international du cancer, Vol. 122, No. 8. (15 April 2008), pp. 1832-1841./ibr /br /The association between alcohol consumption and an increased risk of breast cancer has been established. It is still unclear however, whether this relationship differs across the estrogen receptor (ER) and progesterone receptor (PR) tumors subtypes. To provide a quantitative assessment of the association between alcohol intake and the risk of ER-/PR-defined breast cancer, we conducted a meta-analysis of cohort and case-control studies. Studies were identified by a literature search of PubMed through April 20, 2007 and by searching the reference lists of relevant articles. Summarized risk estimates (REs) with 95% confidence intervals (CIs) were calculated using random-effects models. The summarized results of the meta-analysis comparing the highest versus the lowest consumption categories showed statistically significant higher risks of developing all ER+ (27%), all ER- (14%), ER+PR+ (22%) and ER+PR- (28%), but not ER-PR- tumors. The dose-response meta-analysis showed that an increase in alcohol consumption of 10 g of ethanol per day was associated with statistically significant increased risks for all ER+ (12%), all ER- (7%), ER+PR+ (11%) and ER+PR- (15%), but not ER-PR-. A statistically significant heterogeneity of the REs across all ER+ versus ER-PR- was observed (p(heterogeneity) = 0.02). The summarized results from studies with adjustment for postmenopausal hormone use, body mass index and family history of breast cancer were higher and statistically significantly different from those without. The observed positive associations with alcohol for ER+PR+ and ER+PR- tumors cannot be explained by estrogen-dependent pathway only. Further studies need to clarify the biological mechanisms.br /iR Suzuki, N Orsini, L Mignone, S Saji, A Wolk/i

iBreast cancer research : BCR, Vol. 6, No. 4. (2004), pp. 170-178./ibr /br /The role of specific dietary factors in breast cancer causation is not completely resolved. Results from prospective studies do not support the concept that fat intake in middle life has a major relation to breast cancer risk. However, weight gain in middle life contributes substantially to breast cancer risk. Alcohol is the best established dietary risk factor, probably by increasing endogenous estrogen levels. Hypotheses relating diet during youth to risk decades later will be difficult to test. Nevertheless, available evidence is strong that breast cancer risk can be reduced by avoiding weight gain during adult years, and by limiting alcohol consumption.br /iMD Holmes, WC Willett/i

iCancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, Vol. 13, No. 1. (January 2004), pp. 94-101./ibr /br /Women with high circulating estrogen concentrations have an increased risk of breast cancer; thus, it is important to understand factors, including genetic variability, that influence estrogen concentrations. Several genetic polymorphisms that may influence sex hormone concentrations have been identified, including CYP17 (5'-untranslated region T-->C), CYP19 [intron 4 (TTTA)(n = 7-13) and a 3-bp deletion (-3)], CYP1B1 (Val(432)Leu), and COMT (Val(108/158)Met). We examined associations between these polymorphisms and serum concentrations of estrogens, androgens, and sex hormone-binding globulin and urinary concentrations of 2- and 16alpha-hydroxyestrone in 171 postmenopausal women, using data from the prerandomization visit of an exercise clinical trial. Participants were sedentary, not taking hormone therapy, and had a body mass index >24.0. Compared with noncarriers, women carrying two CYP19 7r(-3) alleles had 26% lower estrone (P < 0.001), 19% lower estradiol (P = 0.01), 23% lower free estradiol (P = 0.01), and 22% higher sex hormone-binding globulin concentrations (P = 0.06). Compared with noncarriers, women carrying at least one CYP19 8r allele had 20% higher estrone (P = 0.003), 18% higher estradiol (P = 0.02), and 21% higher free estradiol concentrations (P = 0.01). Women with the COMT Met/Met genotype had 28% higher 2-hydroxyestrone (P = 0.08) and 31% higher 16alpha-hydroxyestrone concentrations (P = 0.02), compared with Val/Val women. Few associations were found for CYP17 and CYP1B1 or with serum androgen concentrations. This study provides further evidence that genetic variation may appreciably alter sex hormone concentrations in postmenopausal women not taking hormone therapy.br /iSS Tworoger, J Chubak, EJ Aiello, CM Ulrich, C Atkinson, JD Potter, Y Yasui, PL Stapleton, JW Lampe, FM Farin, FZ Stanczyk, A McTiernan/i

iInternational journal of cancer. Journal international du cancer, Vol. 102, No. 2. (10 November 2002), pp. 172-178./ibr /br /Reproductive characteristics, alcohol intake and polymorphisms in genes encoding sex-steroid metabolizing enzymes might influence the risk of hormone-related cancers by changing circulating concentrations of sex hormones. The relationship between these factors and serum concentrations of estradiol, progesterone, androstenedione, testosterone and DHEA was evaluated in a cross-sectional study of 218 pre-menopausal women from Kaiser Permanente Health Plan in Portland, Oregon. Risk factor information was obtained from questionnaires and hormone serum concentrations were determined by radioimmunoassays. Genotypes for CYP11A 5'UTR(tttta)n, CYP17 5'-UTR -34 T>C, CYP19 IVS4(ttta)n, CYP1B1 (L432V and S453N) and COMT (V158M) were determined from genomic DNA samples. Increasing number of full-term pregnancies was associated with a significant decrease in late-follicular progesterone levels (p-trend = 0.03). Increasing alcohol consumption was associated with higher estradiol levels averaged through the menstrual cycle (p-trend = 0.009) and higher progesterone levels during luteal phase (p-trend = 0.04). Androstenedione and testosterone levels were higher among light to moderate drinkers compared to non-drinkers, although we only observe a significant trend with increasing levels of alcohol consumption for androstenedione. Women heterozygous or homozygous for the CYP1B1 L432V or the S453N polymorphisms had increased luteal estradiol levels (p-value = 0.04 for L432V and 0.04 for S453N). None of the other factors evaluated was significantly associated with serum concentration of hormones. In conclusion, results from this cross-sectional study of pre-menopausal women provide support for an association between light to moderate alcohol intake and elevated levels of estrogen and androgen levels. Our data suggest that circulating levels of progesterone might be related to parity and alcohol consumption, however the biological plausibility of the observed associations is unclear. We found little support for an influence of the evaluated genetic polymorphisms in the steroid synthesis and metabolism pathway on serum hormone levels, except for a possible effect of the CYP1B1 L432V and S453N polymorphisms on serum estradiol levels.br /iM García-Closas, J Herbstman, M Schiffman, A Glass, JF Dorgan/i

iEndocr Relat Cancer, Vol. 11, No. 3. (September 2004), pp. 497-522./ibr /br /It is widely believed that ductal breast cancer dissemination involves a succession of clinical and pathological stages starting with carcinoma in situ, progressing into invasive lesion and culminating in metastatic disease. Such changes have frequently been attributed to the sequential acquisition of various alterations in a single cell followed by clonal selection and expansion, thus leading to intra-tumor diversity. According to this multi-step view, extensive genotype and phenotype (marker expression, grade) shift may occur in the same tumor during progression; this may lead to the co-existence of molecularly and/or pathologically different areas within the same lesion. An increasing amount of data of various natures now appear to challenge this concept: only a few distinct 'portraits', in relation to estrogen receptor (ER) status and grade, may be found among tumors. Moreover, although undergoing increasing genetic alteration, most individual lesions largely maintain their phenotype when they evolve from in situ to the metastatic state. While many of the data presented here are related to ductal tumors, lobular cancer is also discussed.br /iM Lacroix, RA Toillon, G Leclercq/i