Shine Chang

Leptin and prostate cancer

Higher prostate cancer mortality rates among US immigrants from countries with lower rates suggest environmental influences on prostate carcinogenesis (e.g., diet, body composition).

Development of a database for assessing dietary phytoestrogen intake

For the past two decades, epidemiologists have observed lower risks of lung, breast, prostate, colon, and other cancers in populations that frequently consume fruits and vegetables. Numerous phytoestrogens have been shown to be anticarcinogenic under experimental conditions and may account for at least part of the cancer-prevention effects of fruit and vegetable consumption. These plant constituents include isoflavonoids, coumestans, lignans, phytosterols, and flavonoids. DietSys, the nutrient analysis program associated with the National Cancer Institute Health Habits and History Questionnaire (HHHQ), and other nationally available nutrient analysis databases do not fully assess these constituents. Therefore, we modified DietSys to include these components in foods on the basis of published values. In addition, as part of an epidemiological study of prostate cancer, we modified the food-frequency component of the HHHQ to include the main foods contributing to phytoestrogen intake. Although there are limitations to the consistency and quality of many of the values because they were gathered from a variety of sources, our approach should provide a useful first tool for assessing the epidemiological association between phytoestrogen consumption and cancer risk. Furthermore, this work has already facilitated the identification of the major dietary contributors with phytoestrogen activity and prioritized future laboratory analyses of specific foods toward the development of a more complete and accurate database.

Low‐dose genistein induces cyclin‐dependent kinase inhibitors and G1 cell‐cycle arrest in human prostate cancer cells

Genistein, a naturally occurring isoflavone found chiefly in soy products, reportedly has antiprostate cancer effects, but the mechanisms underlying these effects are unknown. We studied the antiproliferative and apoptosis‐inducing effects of genistein in the androgen‐sensitive human prostate cancer cell line LNCaP. Viable cell number was assessed by the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay; cell‐cycle progression and apoptosis were evaluated by flow cytometry; apoptosis was also assessed by a histone enzyme‐linked immunosorbent assay; and the expression of several cell‐cycle– and apoptosis‐related genes and their gene products was determined by northern blot analysis, western blot analysis, and/or assays based on polymerase chain reaction. Physiologic concentrations of genistein (≤ 20 μM) decreased LNCaP viable cell number in a dose‐dependent manner, induced a G1 cell‐cycle block, decreased prostate‐specific antigen mRNA expression, and increased p27KIP1 and p21WAF1 (mRNA and protein) but had no effect on apoptosis or the mRNA expression of the apoptosis‐ and cell‐cycle–related markers bcl‐2, bax, Rb, and proliferating cell nuclear antigen. Higher concentrations of genistein (> 20 μM) did induce apoptosis. We conclude that genistein (at physiologic concentrations) exerts potent antiproliferative effects on LNCaP cells by inducing a G1 cell‐cycle block. The antiproliferative effects of genistein may be mediated by increased levels of p27KIP1 and p21WAF1, which are negative cell‐cycle regulators that act as cyclin‐dependent kinase inhibitors and that have been recently linked with prostate carcinogenesis. These findings may provide insights into the mechanisms underlying the apparent antiprostate cancer effects of soy consumption observed in epidemiologic studies. Mol. Carcinog. 29:92–102, 2000.

Associations among physical activity, body mass index, and health-related quality of life by race/ethnicity in a diverse sample of breast cancer survivors

Health‐related quality of life (HRQOL), body mass index (BMI), and physical activity (PA) levels have all been associated with prognosis following breast cancer and may explain partially the higher mortality for breast cancer in certain racial/ethnic subgroups. In this study, associations between PA, BMI, and HRQOL by race were examined in a sample of breast cancer survivors.

Inflammatory breast cancer and body mass index.

PURPOSE No studies have investigated the etiology of inflammatory breast cancer (IBC), the most lethal form of breast cancer. Because high body mass index (BMI) is associated with decreased risk of premenopausal breast cancer but increased risk of postmenopausal breast cancer, we evaluated whether high BMI was a risk factor for IBC. PATIENTS AND METHODS In a case-comparison study, we matched by ethnicity and registration date 68 IBC patients treated at The University of Texas M.D. Anderson Cancer Center from 1985 to 1996 with 143 patients with non-IBC and 134 patients with cancer at sites other than the breast or reproductive tract (non-breast cancer). The non-breast cancer group was used in lieu of a population-based, healthy control group, which was not available. RESULTS IBC patients were younger at menarche and the time of their first live birth than non-IBC and non-breast cancer patients. The proportion of premenopausal IBC patients was higher than the proportion of premenopausal women in the comparison groups, although differences were not significant. There were no differences in height, but IBC patients were heavier (77.6 kg) than non-IBC (70.0 kg) and non-breast cancer patients (68.0 kg). After adjusting for other factors, women in the highest BMI tertile (BMI > 26.65 kg/m2) relative to the lowest tertile (BMI < 22.27) had significantly increased IBC risk (IBC v non-IBC, odds ratio [OR] = 2.45, 95% confidence interval [CI] = 1.05 to 5.73; IBC v non-breast cancer, OR = 4.52, 95% CI = 1.85 to 11.04). This association was not significantly modified by menopausal status and was independent of age at menarche, family history of breast cancer, gravidity, smoking status, and alcohol use. CONCLUSION Our investigation showed that high BMI was significantly associated with an increased risk of IBC. This association did not vary by menopausal status, although IBC patients were more likely to be premenopausal. Confirming our findings and identifying other IBC risk factors may provide directions for future research on the aggressive nature of IBC.

A case-control study of diet and testicular carcinoma

No risk factor other than cryptorchidism has been consistently associated with testicular cancer, and the influence of diet on testicular cancer risk has not been extensively explored. A few studies have found increased testicular cancer risk in men whose diets are high in fat, red meats, and milk or low in fruits and vegetables. We evaluated the relationship of dietary factors and risk of testicular cancer and also examined whether this risk varied by type of testicular cancer. We conducted a hospital-based case-control study at The University of Texas M. D. Anderson Cancer Center (Houston, TX) of 160 testicular cancer cases diagnosed between 1990 and 1996 and 136 friend-matched controls. The results of multivariable logistic regression analysis showed that after adjustment for age, education, income, ethnicity, cryptorchidism, and total daily calories, increasing total fat, saturated fat, and cholesterol consumption were associated with increasing risk of nonseminoma testicular cancer, with odds ratios (ORs) for the highest vs. the lowest quartiles of 6.3, 5.3, and 4.6, respectively. The risk for seminoma testicular cancer marginally increased with increasing intake of total fat and saturated fat, with ORs for the highest vs. lowest quartiles of 1.9 and 2.1, respectively. Higher total fat consumption was nearly significantly related to increased mixed germ cell tumor risk, with an OR for highest vs. lowest quartile of 4.2. This study supports the hypothesis that diet (particularly high fat consumption) increases testicular cancer risk in young men. However, the small sample size and the possibility that these observations may be due to bias indicate that the relationship of diet and testicular cancer risk needs to be further examined within a prospective or incident case-control study.

Poor Adherence to US Dietary Guidelines for Children and Adolescents in the National Health and Nutrition Examination Survey Population

BACKGROUND Poor diet quality in childhood and adolescence is associated with adverse health outcomes throughout life, yet the dietary habits of American children and how they change across childhood and adolescence are unknown. OBJECTIVES This study sought to describe diet quality among children and adolescents by assessing adherence to the 2010 Dietary Guidelines for Americans (DGA) and to determine whether any differences in adherence occurred across childhood. DESIGN, SETTING, AND PARTICIPANTS We employed a cross-sectional design using data from the National Health and Nutrition Examination Survey (NHANES). Of 9,280 children aged 4 to 18 years who participated in NHANES from 2005 to 2010, those with insufficient data on dietary recall (n=852) or who were pregnant or lactating during the time of interview (n=38) were excluded from the final study sample (n=8,390). MAIN OUTCOME MEASURES We measured adherence to the DGA using the Healthy Eating Index 2010 (HEI-2010) and stratified participants into three age groups (4 to 8, 9 to 13, and 14 to 18 years of age). We analyzed each of 12 HEI-2010 components and total HEI-2010 score. RESULTS The youngest children had the highest overall diet quality due to significantly greater scores for total fruit, whole fruit, dairy, and whole grains. These children also had the highest scores for sodium, refined grains, and empty calories. Total HEI-2010 scores ranged from 43.59 to 52.11 out of 100, much lower than the minimum score of 80 that is thought to indicate a diet associated with good health. CONCLUSIONS Overall, children and adolescents are failing to meet the DGA and may be at an increased risk of chronic diseases throughout life. By analyzing which food groups show differences between age groups, we provide data that can inform the development of dietary interventions to promote specific food groups targeting specific ages and improve diet quality among children and adolescents.

Effect of dietary intake of phytoestrogens on estrogen receptor status in premenopausal women with breast cancer

Abstract: Although many dietary studies have focused on breast cancer risk, few have examined dietary influence on tumor characteristics such as estrogen receptor (ER) status. Because phytoestrogens may modulate hormone levels and ER expression, we analyzed ER status and phytoestrogen intake in a case-case study of 124 premenopausal breast cancer patients. We assessed intake with a food-frequency questionnaire and obtained ER status from medical records. Rather than focusing on risk, we evaluated whether low intakes were more strongly associated with ER-negative tumors than with ER-positive disease. In logistic regression adjusting for potential confounders, threefold greater risks of ER-negative tumors relative to ER-positive tumors were associated with low intake of the isoflavones genistein (odds ratio, OR = 3.50; 95% confidence interval, CI = 1.43–8.58) and daidzein (OR = 3.10; 95% CI = 1.31–7.30). Low intake of the flavonoid kaempferol (OR = 0.36; 95% CI = 0.16–0.83), the trace element boron (OR = 0.33; 95% CI = 0.13–0.83), and the phytosterol β-sitosterol (OR = 0.42; 95% CI = 0.18–0.98) were associated with decreased risk of ER-negative tumors relative to ER-positive disease. Other phytoestrogens were not significantly associated with ER status. Thus, in premenopausal patients, some phytoestrogens may affect breast carcinogenesis by influencing ER status. Such findings suggest new directions for mechanistic research on dietary factors in breast carcinogenesis that may have relevance for prevention and clinical treatment.

Inflammatory breast cancer survival: the role of obesity and menopausal status at diagnosis.

No previous studies have evaluated the effect of body size and menopausal status at diagnosis on survival from inflammatory breast cancer (IBC). We evaluated whether obesity and menopausal status had an impact on IBC survival in a cohort of 177 female IBC patients seen from 1974 to 1993 at The University of Texas MD Anderson Cancer Center. Survival time was defined as time from diagnosis until death or censorship at last date of contact. We categorized women by body size by using the National Institutes of Health/National Heart, Lung, and Blood Institutes definitions of obesity as body mass index ((BMI) = weight in kg/(height in m)2) ≥ 30, overweight as 25  ≤ BMI < 30 kg/m2, and normal/lean as BMI <25 kg/m2. Cox proportional hazards analysis, adjusting for axillary lymph node involvement and chemotherapy protocol, revealed a modifying effect of menopausal status at diagnosis on the association between obesity and IBC survival (P = 0.02). Relative to postmenopausal women, premenopausal women had significantly worse survival (hazard ratio (HR) = 1.51, 95% confidence interval (CI) = 1.03–2.22). After stratifying by menopausal status, premenopausal obese women had non-significantly better survival than their leaner premenopausal counterparts (HR = 0.63, 95% CI = 0.34–1.15) while postmenopausal obese women had significantly worse survival than their leaner counterparts (HR = 1.86, 95% CI = 1.02–3.40). These findings suggest that factors associated with larger body size at diagnosis may contribute to shorter IBC survival among postmenopausal women but not premenopausal women, who were found to have poorer survival regardless of body size.

Mechanistic studies of the effects of the retinoid n-(4- hydroxyphenyl)retinamide on prostate cancer cell growth and apoptosis

To explore the mechanisms underlying the chemopreventive effects of the synthetic retinoid N‐(4‐hydroxyphenyl)retinamide (4‐HPR) in prostate cancer, we evaluated the anti‐proliferative and apoptosis‐inducing effects of 4‐HPR in the androgen‐sensitive human prostate cancer cell line LNCaP. 4‐HPR decreased the number of viable LNCaP cells (as measured by the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay) in a dose‐dependent manner. Although 4‐HPR exerted a modest G1 cell‐cycle block (as determined by flow cytometry), its effect on reduced cell number appeared to result primarily from induction of apoptosis (as measured by an enzyme‐linked immunosorbent assay and flow‐cytometric assays). The mitogenic effects of R1881, a non‐metabolizable androgen that potently induces LNCaP cell proliferation, was completely blocked by greater than 0.5 μM 4‐HPR. Furthermore, increasing the R1881 concentration in the presence of 2.0 μM 4‐HPR increased apoptotic cell death. 4‐HPR decreased prostate‐specific antigen (PSA) protein levels in conditioned medium and decreased PSA mRNA expression. 4‐HPR also decreased the ratio of bcl‐2 to bax mRNA expression in LNCaP cells by approximately 45%, indicating that the apoptotic effects of 4‐HPR may be mediated, at least in part, by alterations in the bcl‐2/bax–regulated apoptotic pathway. N‐acetylcysteine (4 mM) completely blocked the anti‐proliferative and apoptotic‐inducing effects of 4‐HPR, suggesting that an oxidative mechanism may be involved. We concluded that (i) 4‐HPR exerts growth‐suppressive and apoptotic effects on LNCaP cells, (ii) 4‐HPR can interact with androgen to suppress proliferation and induce apoptosis, (iii) the apoptotic effects of 4‐HPR may be mediated in part by the bcl‐2/bax pathway, and (iv) a pro‐oxidant mechanism may contribute to the anti‐proliferative and apoptotic‐inducing effects of 4‐HPR. Mol. Carcinog. 24:160–168, 1999.