Over 60% of U.S. adults are either overweight or obese. The effect of obesity on cancer mortality is striking: approximately 90,000 deaths per year from cancer may be avoided if Americans could maintain a BMI of <25.0 throughout adulthood. The aim of this research was to employ and evaluate energy balance interventions designed to reverse obesity-related risk factors. The overarching hypothesis was that energy balance interventions would reduce cancer risk. To test this hypothesis, we used mostly animal models of diet-induced obesity and tested the effect of a low carbohydrate diet, calorie restriction, and exercise on adiposity, levels of circulating hormones, insulin resistance, and oxidative stress. To extend on in vivo findings from the final animal study, we utilized a human breast cancer cell line to further characterize the gene expression of thioredoxin-interacting protein in the context of p53 deficiency. Calorie restriction was the most potent energy balance intervention. It caused weight loss, slowed tumor growth, reduced circulating IGF-1 and leptin levels, improved insulin resistance, and elicited a robust transcriptional response in visceral white adipose tissue following weight loss. Although a low carbohydrate diet and exercise did decrease hormones associated with obesity, (IGF-1 and leptin respectively) calorie restriction proved to be the most effective at reducing multiple obesity-related factors. Finally, from our studies analyzing the effect of obesity and exercise on oxidative stress in the context of p53-deficiency, we discovered that thioredoxin-interacting protein is transcriptionally upregulated in response to increased glucose flux associated with metabolic dysregulation that occurs as a consequence of loss of p53. / text

Advancements in medicine and technology have led to an increasing number of cancer survivors. The development of a second primary cancer is one of the most severe sequelae of a cancer diagnosis, particularly for cancers that lack an effective screening tool as with ovarian cancer. Breast and ovarian cancer are major causes of morbidity and mortality in women; in the U.S., breast cancer has the highest incidence in women and ovarian cancer is the most fatal of gynecological cancers. Further, these two cancers have been found to co-occur. Along with possible treatment effects of the first cancer, shared risk factors, shared genetics, and interactions between these two have been hypothesized to contribute to their co-occurrence. Research on shared risk factors for second cancers is lacking and being able to identify potentially modifiable factors associated with second primary cancer could improve clinical recommendations for cancer survivors. Therefore, this dissertation examined risk factors for the development of double primary breast and ovarian cancer (DPBOC) in three parts 1) a comprehensive review of the literature to identify studies assessing risk factors for DPBOC, 2) a case-control study assessing the association between three potentially-modifiable risk factors (oral contraceptive (OC) use, parity, and breastfeeding), and risk of second primary ovarian cancer following breast cancer (BR-OV), second primary breast cancer following ovarian cancer (OV-BR), single primary ovarian cancer (OV), and single primary breast cancer (BR), and 3) a cohort study assessing OC use, parity, and breastfeeding and risk of BR-OV, OV, and BR. The comprehensive review identified few studies assessing epidemiologic risk factors for the development of DPBOC and most of the findings were not statistically significant. The majority of studies focused on treatment of breast cancer and risk of second primary ovarian cancer. While most of the findings on chemotherapy, radiotherapy, and Tamoxifen were heterogeneous and lacked statistical significance, hormone therapy for breast cancer may be associated with an increased risk of second primary ovarian cancer. The majority of studies on genetic risk factors for DPBOC looked at BRCA1/2 mutations or a crude measure of family history. Both BRCA1/2 and family history were consistently associated with risk of DPBOC, but studies varied on the extent of this risk due to differences in study design, exposure and outcome definition, and statistical power. No studies were identified examining DNA methylation and risk of DPBOC. The case-control study used data from the three clinic-based sites of the Breast Cancer Family Registry (BCFR) which consisted of women from breast and ovarian cancer families. We observed an inverse association with both OC use (OR=0.38, 95% CI: 0.22, 0.60) and breastfeeding (OR=0.52, 95% CI: 0.31, 0.87) and risk of DPBOC, but a positive association with parity (≥2 full-term pregnancies: OR=5.78, 95% CI: 2.82, 14.58), regardless of diagnosis order (BR-OV or OV-BR). We found similar associations for our OV and BR outcomes as well. When we examined differences between high and average risk women (using BRCA1/2 mutation status and predicted lifetime risk of breast or ovarian cancer), the inverse association with OC use only remained in women at average risk while the inverse association with breastfeeding only remained in women at high risk. As the positive association with parity and all of our outcomes disagreed with our hypothesis we conducted several sensitivity analyses to explore this finding. Survivor bias may have influenced our results as we observed differences in our findings between cases diagnosed ≤2 or ≤5 years before the baseline interview (pseudo-incident) and cases diagnosed >2 or >5 years before the baseline interview (prevalent). Specifically, the inverse association with OC use and all of our outcomes, and the positive association with parity and all of our outcomes were attenuated in the pseudo-incident group. To address concerns of selection and information bias in our case-control study, we conducted a cohort study using data from The Breast Cancer Prospective Family Study Cohort (ProF-SC). In contrast to our case-control findings, we observed a suggestive positive association between OC use and risk of BR-OV (HR=1.62, 95% CI: 0.91, 2.90) which became stronger in women at high risk, and an inverse association between having two or more full-term pregnancies compared to nulliparous and risk of BR-OV (HR=0.47, 95% CI: 0.22, 0.97) which did not vary by underlying risk of breast and ovarian cancer. However, our BR-OV results may have similarly been influenced by survivor bias as we observed differences in our results between our pseudo-incident and prevalent BR-OV cases; the association between OC use and BR-OV only remained in the prevalent cases. In summary, the results of this dissertation highlight the methodological challenges in the study of second primary cancers and the importance of considering survivor bias in a cohort of cancer survivors being followed for second cancers. Further, our results are suggestive of a discordant effect of OC use on first primary versus second primary ovarian cancer which should be explored in future studies.

No description available.

Background: Breast cancer is the most frequent female cancer in both developed and developing world which comprising 16% of all female cancer according to WHO GLOBOCAN 2008. The statistic from Hong Kong Cancer Registry reported that breast cancer is the third commonest cause of female death in Hong Kong. Breast cancer incidence varies remarkably among developed countries. The high dietary consumption of soy isoflavones has been hypothesized to explain the lower breast cancer incidence among women in Asian countries in observational studies, but whether soy isoflavones exert estrogenic or anti-estrogenic in breast tissue remains uncertain. Objective: This systematic review was to assess the effects of isoflavone-rich soy consumption on breast cancer risk in pre- and post-menopausal women Methods: Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines for conducting and reporting randomized controlled trials were followed. Data sources: A systematic review of randomized controlled trials was conducted through searching databases: MEDLINE, PubMed and Cochrane Library (2002 until March 2012). Keywords for electronic searches included: [(soy OR isoflavones) AND (breast cancer OR breast neoplasms)] limited study types to human & randomized controlled studies. Study selection: RCTs of the effects of isoflavones or supplement versus placebo or control diet among pre- and post-menopausal participants who were currently free from breast cancer. Outcome measurements: serum sex hormones and IGF profile, mammographic density and menstruation cycle length Results: 15 RCTs (1527 women) compared isoflavones with placebo or control diet for study duration ranged from 2 months to 2 years. No significant effect was found on serum sex hormones, IGF profile, mammographic density or menstrual cycle length. The effect of menstrual cycle on mammographic densities was noticed. Conclusion: The results of the systematic review did not support the hypothesis that short-term isoflavones exposure has an effect on modulating breast cancer risk. The effect of menstrual cycle on mammographic densities probably reflects the effect of hormonal changes. Null results did not necessarily contradict the inverse association between soy intake and breast cancer risk from the results of epidemiologic studies. The absence of conclusive data on the effects might be attributable to the insufficient exposure duration in the RCTs. Longer duration of soy exposure and early life exposure might be a scope for future research. / published_or_final_version / Public Health / Master / Master of Public Health

No description available.

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%.

Large bowel cancer, or colorectal cancer (CRC) is the third most common cause of cancer worldwide and the fourth biggest cause of cancer mortality. Twin studies have shown that the heritable contribution is ~35%, with ~5% of cases due to rare, high-penetrance mutations. In the last decade, the use of genome-wide association studies on large, well-characterised case-control cohorts of CRC has facilitated the identification of over 25 common genetic variants that carry with them an increased predisposition to colorectal cancer, invoking the common-disease common variant paradigm. As almost all of these variants lie within non-coding regions, the underlying causal mechanism is to-date poorly understood for the majority of these loci, and it is thought that they mediate risk by influencing gene expression levels. To test this hypothesis, an agnostic approach that utilises expression quantitative trait loci (eQTL) analysis was first carried on 115 normal colorectal mucosa samples and 59 peripheral blood mononuclear cells (PBMC). As these heritable variation on gene expression are likely to be subtle, there is a strong emphasis on the technical methodology to minimise experimentally-induced non-biological variations, including the extraction of high-quality RNA from primary tissue, the selection and validation of reference genes for normalisation of gene expression quantification, as well as internal validation of the samples and data processing. Thereafter, the association between the 25 CRC risk variants and the expression of their cis-genes were examined systematically, demonstrating that ten of these variants are also tissue-specific eQTLs. This intermediate phenotype strongly suggests that they confer risk, at least in part, by modifying regulatory mechanisms. One of the best eQTL associations (Xp22.2) is investigated in further detail to reveal a novel indel polymorphism (Indel24) at the distal promoter region of target gene SHROOM2 that influenced both transcript abundance and CRC risk more than the original tagging SNP. Functional verification with gene reporter assays indicated that Indel24 displays differential allelic control over transcriptional activity. Further in silico analysis and mutations to the reporter gene constructs provided evidence that Indel24 modulates transcription by modifying the spacing between CCAAT motifs and the consequent binding affinity of NF-Y transcription factor. siRNA depletion of NF-Y was associated with a reduction in transcriptional activity of the Indel24 gene construct as well as endogenous SHROOM2, which is strongly supportive of the interaction between Indel24 and NF-Y in the transcriptional activation of SHROOM2. Preliminary evidence is suggestive of SHROOM2 being expressed at the top of the intestinal epithelial crypt and playing a role in cell cycle regulation. Hypothesis-driven approaches can also be of utility in demonstrating functionality of CRC risk variants, complementing the hypothesis-free approach of eQTL analysis. Guided by a recently discovered gene-environment interaction between the 16q22.1 risk variant and circulating vitamin D levels, the influence of the rs9929218 SNP on CDH1 gene expression was examined, in relation to the expression of putative regulatory genes derived from in silico analysis and studies of other target genes. Although there was no direct association between rs9929218 and CDH1 expression, there were multiple two-way interactions that were together suggestive of rs9929218 influencing the VDR/FOXO4 regulation of CDH1. This provides functional support for the mechanism underlying the epidemiological observation of the gene-environment interaction between 16q22.1 and vitamin D, and demonstrates a candidate-based approach in deciphering the link between genetic locus and CRC susceptibility. In summary, the research presented in this thesis has validated the experimental rationale of utilising expression studies of normal colorectal mucosa to hone in on the molecular mechanisms and susceptibility genes underlying the association between common genetic variation and CRC risk.

A pilot study was conducted to evaluate whether premenstrual syndrome was a risk factor for breast cancer among premenopausal women. As subjects, 54 women between the ages of 26 and 46 years, each diagnosed with breast cancer, were compared to three separate control groups, consisting of 193 female patients seen in medical offices for routine physical exams, 51 female nursing students, and 559 female graduate students. Each eligible subject was either mailed or personally given a survey questionnaire probing premenstrual and menstrual symptomatology and general descriptive characteristics. An association between premenstrual syndrome and breast cancer was evaluated by estimating exposure odds ratios and associated confidence intervals. Analysis of the data suggested that premenstrual syndrome did not pose a breast cancer risk among premenopausal women. / Graduation date: 1993

Objectives To evaluate the association between exposures to the main chemical contaminants released by the industry in freshwater and the rise in cancer cases among the population in China. Methods A systematic review was undertaken of the scientific literature compiled in the MEDLINE (via PubMed©), Google scholar, Web of Knowledge. The descriptors used were "cancer", "water pollution”, “industry” and “chemical", limited to studies that relevant to the research questions. Articles selected were of any type in English, from the inception of the indexing of the primary source until July 28th of 2013. With the quantitative data, Health impact assessment formulas are developed and then applied to subsequent data to make estimate. Results The search generated 306 articles, from which 10 were selected after applying the inclusion and exclusion criteria. The analysis of freshwater contaminants that attributed to industry in this review included aromatic amine, vinyl chloride, benzene, hexavalent Chromium, dioxin, and others of industrial origin. The majority of the studies find a significant link between exposure to drinking water contaminants and the increase in cancer cases, especially in the rural areas. In some of the studied populations a significant dose-response relationship was observed. Discussion After reviewing the included studies and the estimation of health impact assessment, I concluded that the association between cancer risks and industrial contamination in freshwater resources in China does indeed exist. While there are several other factors that interact the cancer risks, such as agriculture related water pollution and rapid growth of population. Taking into account that most of the articles were located in western countries, more Chinese studies are required in order to know the effect of freshwater contamination on cancer risks, in particular among those who lived in rural industry area. Conclusion This study provides the first estimated health impacts based on the relationship between industrial freshwater pollution and cancer risks, supporting decision makers to formulate public health recommendations to ensure a safer and healthier environment in the future. However, further study is critically needed for the prevention of this form of contamination. / published_or_final_version / Public Health / Master / Master of Public Health

Background: Although some classic risk factors of NPC such as salted fish, tobacco and vegetable consumption were established a few decades ago, no convincing evidence that the decreasing trend in NPC incidence and mortality rates seen in most parts of the world could be explained by the changes of these consumption. As different histological types and age groups may have distinct risk factor profile in NPC development, it is important to look at incidence and mortality trends across different jurisdictions before any further individual studies are carried out worldwide. Objectives: With the focus on both high and low risk areas, this study aimed to 1) examine the descriptive epidemiology of NPC, including the secular trends of age-standardised incidence rate (ASIR), age-standardised mortality rate (ASMR) and age-specific incidence and mortality rate by sex; 2) perform an ecologic analysis between ASIR, ASMR and classical exposures. This included a multi-jurisdiction comparison between ASIR, ASMR and salted fish, cigarette and vegetable consumption per capita and 3) investigate the secular trend of ASIR and ASMR by sex, age and histologic subtype. Methods: NPC ASMR was obtained from the WHO cancer mortality database and ASIR, age-subtype specific incidence and mortality rates were provided by various cancer registries. All age and subtype specific rates were plotted in every 5 calendar years. Per capita consumption of salted fish, tobacco and vegetables in 8 regions (Hong Kong, China, Finland, Japan, Portugal, Singapore, United Kingdom and United States) were obtained from the Food and Agriculture Organization of the United Nation (FAO) and from different corresponding governmental departments. Pearson correlation coefficients and multivariate regression analysis were performed to examine both crude and adjusted associations. Results: There were markedly decreasing trends of NPC ASIR and ASMR in most of the high risk areas over the past three decades, while only some declines in incidence and mortality rates was observed in low risk areas. No association was found between salted fish, vegetable consumption and ASMR or ASIR in any region, except in Hong Kong where lag year cigarette consumption in males was correlated with ASIR (Pearson r for 10 lag year = 0.680; 15 lag year = 0.739 and 20 lag year = 0.747, all p<0.05). Multivariate regression analysis did not show association with any of the consumption in Japan, Portugal, the US and the UK. An earlier age of onset around 45-50 was observed with non-keratinizing carcinoma as the dominant subtype in high risk areas, while in low risk area the peak age was not seen until after 60 years old with most of the cases being keratinizing NPC. Conclusions: There were distinct differences in risk profile between NPC age-standardised and age-subtype specific rates between high and low risk areas. With the general secular trends of NPC incidence and mortality rates by age and tumour type being revealed in this study, further exploration in other jurisdictions with different potential risk or protective factor is warranted. / published_or_final_version / Public Health / Master / Master of Philosophy