Breast cancer incidence, particularly late-stage disease, is increasing in U.S. women under 40 years of age, pointing to the importance of exposures acting early in the life course to increase breast cancer risk. Earlier onset of breast development has recently been identified as an independent risk factor for breast cancer. Thus, identifying modifiable factors that can delay the onset of breast development may provide an opportunity for breast cancer primary prevention starting early in life. This dissertation examined the influence of the early-life environment on the age at onset of breast development through: 1) a systematic review of the literature relating maternal pre-pregnancy body size, gestational weight gain (GWG), birth size, and infant growth to the timing of breast development and menarche; 2) analyses assessing the associations between these factors and the onset of breast development in a pubertal cohort enriched for breast cancer family history (BCFH); and 3) a pilot study assessing whether these factors are associated with serum levels of insulin-like growth factor(IGF)-1 and insulin-like growth factor binding protein(IGFBP)-3 during puberty. Our systematic review identified 96 studies, the majority of which examined the association between birthweight and age at menarche. Although low birthweight is often cited as a risk factor for early menarche, the majority of studies (40/73 total) that examined this association did not observe a statistically significant association. Differences in exposure assessment, inadequate control for confounders, and differences in postnatal growth across studies may drive inconsistencies in the birthweight literature. In contrast, higher maternal body mass index (BMI) prior to pregnancy, GWG in excess of recommended guidelines and faster rates of weight gain between birth and 2 years of age were consistently associated with earlier age at breast development and menarche. We used data from the LEGACY Girls Study, a prospective cohort of girls primarily ages 6-13 years at baseline in which approximately 50% of girls had a family history of breast cancer, to examine the relations between maternal factors, birth size and infant growth and the onset of breast development, defined as a maternal report of breast Tanner stage 2 or greater. Daughters of women with a pre-pregnancy BMI of 25 or greater and who gained 30lbs or more during pregnancy experienced breast development at an earlier age than daughters of women with a pre-pregnancy BMI less than 25 and who gained less than 30lbs. This association was similar in girls with and without a BCFH. Birthweight and birthlength were not associated with the timing of breast development. In a subset of LEGACY girls with height and weight data during infancy available from medical records, we examined the associations between changes in weight-for-age and length-for-age Z-scores from birth to 1 year of age and the onset of breast development. We observed a modest association between faster rates of weight gain from 0-12 months and earlier age at breast development. When we examined smaller age intervals within infancy, faster weight gain from 2-4 months and 6-9 months were each associated with an earlier age at breast development. A similar pattern was observed for growth in length, and these associations did not vary by BCFH. In our pilot study including 109 girls with available serum samples between 6-17 years of age at the LEGACY New York site, rapid weight gain from 0-12 months was associated with higher mean levels of IGF-1 relative to IGFBP-3. Although not statistically significant, girls with a maternal pre-pregnancy BMI≥25 and GWG≥30lbs also had higher mean levels of the IGF-1/IGFBP-3 ratio. Since serum IGF-1 and IGFBP-3 are objective measures that are known to increase rapidly during puberty, the results of our pilot study support that the maternal BMI, GWG and rapid infant weight gain are associated with biological changes in the girls. Our findings suggest that measurement error in outcome assessment or confounding did not drive the associations that we observed between these factors and earlier onset of breast development. In conclusion, we identified higher maternal pre-pregnancy BMI, excess GWG and rapid growth during infancy as modifiable factors associated with earlier onset of breast development in girls across the spectrum of familial risk for breast cancer. While this suggests that modifying these factors may decrease breast cancer risk later in life, further research should consider additional and potentially opposing pathways, such as childhood body size, through which the early-life environment affects breast cancer risk.

Background: Estrogen receptor (ER)- and progesterone receptor (PR)-negative (ER-PR-) breast cancer is associated with higher grade and poorer prognosis compared with other breast cancer subtypes. High parity, coupled with lack of breastfeeding, has been associated with an increased risk of ER-PR- cancer. The mechanism of this etiology is unclear, and may be obfuscated by ER and PR correlation with each other as well as other prognostic tumor characteristics. Methods: Using population-based and clinic-based ascertained cases and controls from the Breast Cancer Family Registry, I examined reproductive risk factors, including parity, breastfeeding, and oral contraceptive (OC) use, in relation to ER and PR status, using polytomous logistic regression (for the population-based data) and the method of generalized estimating equations (GEE) (for the clinic-based data) as well as the pseudo-conditional likelihood approach, which accounts for correlated outcome variables. Results: High parity (≥ 3 live births) combined with lack of breastfeeding, was positively associated with ER-PR- tumors (odds ratio [OR]=1.57, 95% confidence interval [CI] 1.10-2.24, population-based cases vs. controls) relative to nulliparity. There was no association with ER-PR- tumors and parity in women who breastfed (OR=0.93, 95%CI 0.71-1.22) relative to nulliparous women. Associations with ER-PR- cancer were higher across all races/ethnicities among women who did not breastfeed compared with women who did. Population-based and clinic-based data were generally in agreement (OR=2.07, 95% CI 1.09-3.91, clinic-based cases vs. controls, relative to nulliparity). When adjusted for the correlation of PR-status and grade, to ER-status, the association between high parity +lack of breastfeeding and ER- status, was maintained. OC use before year 1975 was associated with an increased risk of ER-PR- tumors (OR=1.32, 95% CI 1.04-1.67, population-based data, cases vs. controls) relative to never use of OCs. For women who began OC use in 1975 or later there was no increased risk. Analysis of OC use in clinic-based data agreed with the findings of the population-based data. Conclusions: My findings support that there are modifiable factors for ER-PR- breast cancer, and that breastfeeding in particular may mitigate the increased risk of ER-PR-cancers seen from multiparity. The mechanism of both risk and risk mitigation may operate primarily through the estrogen, rather than progesterone, pathway.

Indiana University-Purdue University Indianapolis (IUPUI) / Perfluorooctanoic acid (PFOA) is a synthetic organic chemical that consists of an 8 carbon alkyl chain with a terminal carboxyl group in which the carbon-hydrogen bonds have been replaced with carbon-fluorine bonds except at the terminal carboxyl end. This perfluoralkyl carboxylate is a contemporary synthetic chemical that does not occur naturally in the environment and has only seen widespread use within the last 50 years. PFOA is environmentally persistent and is ubiquitously found in human serum. PFOA has been shown to induce a tumor triad consisting of liver adenomas, Leydig cell adenomas and pancreatic acinar cell tumors in male Spraque-Dawley rats. The ability of PFOA to produce tumors in rodents compounded by the fact that PFOA is accumulating not only in those occupationally exposed, but also in the general population, justifies concern about the carcinogenic potential of PFOA in humans. This paper reviews the data from current published research and reveals that some carcinogenic pathways identified in the tumors produced by PFOA in experimental animals may provide a plausible mode of action for human carcinogenesis.

Indiana University-Purdue University Indianapolis (IUPUI) / Hispanics are more likely to die from breast cancer compared to non - Hispanic whites matched on stage and age at diagnosis. Higher mortality rates among Hispanics are attributed to cancer - related disparities across the cancer continuum including later - stage detection. While research has shown that socioeconomic factors play a significant role in the development and maintenance of cancer - related disparities, differences persist when these factors are controlled. Thus far, research on cultural factors and cognitions surrounding cancer is limited. The current study investigated illness representations of cancer and their determinants among Hispanic men and women (N = 120) using a cross - sectional survey approach. The study sample was comprised of predominantly first generation, employed Hispanic women in their early - thirties from Mexico. Most had not resided in the U.S. for more than 5 - 9 years. Half of the sample reported an annual income of $20,001 - $30,000 and completing at least a middle school education. While the majority indicated that they did not have health insurance, most indicated that they did have a regular source of health care. Additionally, while most had not been diagnosed with cancer, nearly half of the sample knew of someone diagnosed with cancer. Descriptive data regarding illness identity, illness coherence, timeline, causes, consequences, and controllability are provided. Results suggest that demographic factors (i.e. acculturation, education, and income), cultural constructs (i.e. fatalism and familism), intrapersonal factors (state and trait anxiety), and previous experience with cancer were associated with illness representations of breast cancer. The study adds to theliterature by systematically investigate illness representations of breast cancer and their determinants among a diverse sample of Hispanic men and women. This is a significant first step that can be used to guide and develop effective and culturally appropriate interventions that ultimately reduce disparities across the cancer continuum.

This study investigated potential apoptotic and anti-proliferative effects of the phytochemicals, genistein and anthocyanin extract, as single and combined treatments in MCF-7 human breast cancer cells. Cells were exposed to single and combined treatments with the phytochemiclas for 48 and 72 hours. Cell viability was assessed using the MTT bioassay. Apoptosis induction was assessed using acridine orange ethidium bromide and rhodamine 123 ethidium bromide fluorescence assays. Both singe and combination treatments induced dose- and time-dependent apoptotic cell death in MCF-7 cells. The percentage of apoptosis was higher in combination treatments than single treatments with either phytochemical, although the difference was not statistically significant. The combination of genistein and anthocyanin extract peaked in efficacy at 48 hours of treatment, to exhibit significantly greater (P<. O5) dose- and time-dependent cell cytotoxicity than single treatments. This study reveals potential chemopreventive implications for the complementary effects of genistein and anthocyanin extract. / by Corine M. Stinson. / Thesis (M.S.)--Florida Atlantic University, 2011. / Includes bibliography. / Electronic reproduction. Boca Raton, Fla., 2011. Mode of access: World Wide Web.

Secular trends in breast cancer incidence in younger women suggest environmental factors, like exposure to environmental chemicals, may play a role in rising incidence. One of the strongest risk factors for developing breast cancer, next to family history, is high mammographic breast density, which is defined as the proportion of fibroglandular breast tissue relative to fat as seen on a mammogram. Phthalates, a ubiquitous endocrine disrupting chemical, have the potential to interfere with endogenous hormones like estrogen and androgens. There is growing evidence from animal and epidemiologic studies indicating distinct periods of heightened susceptibility to endocrine disrupting chemicals throughout the life course, particularly during critical windows of breast development. Exposure to hormonally active environmental chemicals like phthalates may be a modifiable risk factor for breast cancer, therefore reducing or eliminating exposure could have substantial public health benefits. The overarching goal of this dissertation was to assess the relationship between exposure to phthalates during two critical windows of susceptibility, the prenatal and pregnancy periods, and its effect on breast tissue composition in adolescence and adulthood. First, a comprehensive review of epidemiologic studies summarized the body of evidence for the association between phthalate exposure and intermediate markers known to be in the causal pathway of breast cancer risk (age at breast development, menarche, and breast tissue composition). This systematic review of the literature aimed to identify potential patterns of evidence by outcome and timing of exposure. Evidence from this review suggested that phthalate exposure during the prenatal and childhood periods may play a role in altering menarche. Findings for phthalate exposure and age at breast development were inconclusive. There was a considerable lack of epidemiologic data on phthalate exposure and breast tissue composition throughout the life course. Based on one study, there is a potential association between phthalate exposure during pre-puberty and altered breast tissue density in adolescent girls. No study assessed the relationship between phthalate exposure during the prenatal or pregnancy period and subsequent breast tissue composition. Second, an examination for the association between prenatal phthalate exposure and breast tissue composition measured in adolescence (Chapter 3) and the association between phthalate exposure during pregnancy and breast tissue composition measured during or after the postpartum transient period (Chapter 4) aimed to address this major gap identified from the comprehensive review. The empirical chapters of this dissertation used data from an ongoing longitudinal birth cohort study of mothers and their children conducted by the New York City Columbia Center for Children's Environmental Health and the Breast Cancer and the Environment Research Project (CCCEH-BCERP). The CCCEH-BCERP study cohort has prospective data on nine phthalate metabolite concentrations measured during the third trimester of pregnancy and breast tissue composition measured in a subsample of mother-daughter dyads. Notably, we used novel non-invasive methods (optical breast spectroscopy) in this younger cohort of mothers and daughters to objectively measure specific components of the bulk breast composition before mammography screening age. There was significant evidence of altered breast tissue composition in both mothers and daughters. For daughters (n=127, mean age 15.2 ± 1.9 years), prenatal exposures to select low molecular weight (LMW) and high molecular weight (HMW) phthalate metabolites altered overall breast density in opposing directions, which appears to be driven by significant altered percent breast water. There was a significant association between higher prenatal levels of a LMW phthalate metabolite (monobutyl phthalate) and lower levels of overall breast density (adjusted β = -0.32; 95% CI: -0.51, -0.13) and significant association between sum of di(2-ethylhexyl) phthalate (∑DEHP), a HMW phthalate metabolite, and higher levels of overall breast density in girls (adjusted β = 0.20; 95% CI: 0.05, 0.34). For mothers (n=133, mean age 41 ± 5.3 years at follow-up), there was a significant association between two LMW phthalate metabolites and lower levels of percent breast collagen. Additionally, there was a significant inverse relationship between levels of mono-(3-carboxypropyl), a HMW phthalate metabolite, and percent total hemoglobin of the breast (adjusted β =-0.03; 95% CI: -0.06, 0.00, p=0.05). Overall, this dissertation increased our understanding of the impact that exposure to phthalates during critical windows of susceptibility may have on specific components of the breast. Reducing exposure to both HMW and LMW phthalates may have an impact in reducing breast cancer risk, particularly for girls prenatally exposed, as there was stronger evidence of higher overall breast density and percent water from exposure to select HMW phthalates. Future prospective studies should confirm these results as findings might provide an opportunity for modifying potential breast cancer risk.

Breast cancer is the most common cancer and the second most common cause of cancer death in women. In 2008 there were 182,460 women diagnosed with breast cancer, and 40,480 women died of this disease. Breast cancer can be prevented by medical (tamoxifen or raloxifene) or surgical approaches (bilateral mastectomy or oophorectomy). Prevention is only recommended for women at high risk for developing breast cancer; therefore, proper risk calculation is essential in identifying women that may benefit from prevention measures. There is an easy-to-use and easily accessible risk calculation tool for determining a woman's risk of developing breast cancer and need for referral for counseling, gene testing, and possibly preventive therapy. This article reviews the components of risk assessment, the most frequently used risk calculation tool, and approaches to breast cancer risk reduction including medical and surgical therapies. The use of these therapies results in a risk reduction of 50-90%.

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This thesis examines cancer and mortality rates among people diagnosed with hepatitis B (HBV) and C (HCV) infection in New South Wales (NSW) from 1990 through 2002, by linking hepatitis notifications with the NSW Central Cancer Registry (CCR) and National Death Index. Of the 39101 HBV, 75834 HCV and 2604 HBV/HCV co-infection notifications included 1052, 1761 and 85 were linked to cancer notifications and 1233, 4008 and 186 were linked to death notifications respectively. Of 2072 hepatocellular carcinoma (HCC) notifications to the CCR 323, 267 and 85 were linked to HBV, HCV and HBV/HCV co-infection notifications. Incidence of HCC was 6.5, 4.0 and 5.9 per 1000 person years for HBV, HCV and HBV/HCV co-infected groups. Risk of HCC in those diagnosed with hepatitis was 20 to 30 times greater than the standard population. There was a marginally statistically significant increased risk of immunoproliferative malignancies associated with HCV infection (SIR=5.6 95% CI 1.8 ???17.5). Risk of death for those with hepatitis was significantly greater, 1.5 to 5 fold, than the general population with the greatest risk among those with HBV/HCV co-infection. The primary cause of HBV deaths was liver related, particularly HCC, whereas in the HCV groups drug related deaths were most frequent. Among people with HCV, risk of dying from drug related causes was significantly greater than from liver related causes (p=0.012), with the greatest increased risk in females age 15- 24 years (SMR 56.9, 95%CI 39.2???79.9). Median age at diagnosis of HCC varied markedly by country of birth and hepatitis group: HBV 66, 63 and 57years ; HCV 51, 68 and 71 years; unlinked 69, 70 and 64 years for Australian, European, and Asian-born groups, respectively (P<0.0001 for all groups). While the risk of cancer, particularly HCC, is elevated among people with HBV and HCV infection, the absolute risk remains low. Young people with HCV face a higher mortality risk from continued drug use than from liver damage related to their HCV infection. The influence of IDU in the epidemiology of HCC in New South Wales was possibly reflected in the varying distributions of age and country of birth.

This thesis examines cancer and mortality rates among people diagnosed with hepatitis B (HBV) and C (HCV) infection in New South Wales (NSW) from 1990 through 2002, by linking hepatitis notifications with the NSW Central Cancer Registry (CCR) and National Death Index. Of the 39101 HBV, 75834 HCV and 2604 HBV/HCV co-infection notifications included 1052, 1761 and 85 were linked to cancer notifications and 1233, 4008 and 186 were linked to death notifications respectively. Of 2072 hepatocellular carcinoma (HCC) notifications to the CCR 323, 267 and 85 were linked to HBV, HCV and HBV/HCV co-infection notifications. Incidence of HCC was 6.5, 4.0 and 5.9 per 1000 person years for HBV, HCV and HBV/HCV co-infected groups. Risk of HCC in those diagnosed with hepatitis was 20 to 30 times greater than the standard population. There was a marginally statistically significant increased risk of immunoproliferative malignancies associated with HCV infection (SIR=5.6 95% CI 1.8 ???17.5). Risk of death for those with hepatitis was significantly greater, 1.5 to 5 fold, than the general population with the greatest risk among those with HBV/HCV co-infection. The primary cause of HBV deaths was liver related, particularly HCC, whereas in the HCV groups drug related deaths were most frequent. Among people with HCV, risk of dying from drug related causes was significantly greater than from liver related causes (p=0.012), with the greatest increased risk in females age 15- 24 years (SMR 56.9, 95%CI 39.2???79.9). Median age at diagnosis of HCC varied markedly by country of birth and hepatitis group: HBV 66, 63 and 57years ; HCV 51, 68 and 71 years; unlinked 69, 70 and 64 years for Australian, European, and Asian-born groups, respectively (P<0.0001 for all groups). While the risk of cancer, particularly HCC, is elevated among people with HBV and HCV infection, the absolute risk remains low. Young people with HCV face a higher mortality risk from continued drug use than from liver damage related to their HCV infection. The influence of IDU in the epidemiology of HCC in New South Wales was possibly reflected in the varying distributions of age and country of birth.