Shahnjayla K. Connors

New Insights Into the Mechanisms of Green Tea Catechins in the Chemoprevention of Prostate Cancer

Prostate cancer is the most commonly diagnosed cancer and second most common cause of cancer deaths in American men. Its long latency, slow progression, and high incidence rate make prostate cancer ideal for targeted chemopreventative therapies. Therefore, chemoprevention studies and clinical trials are essential for reducing the burden of prostate cancer on society. Epidemiological studies suggest that tea consumption has protective effects against a variety of human cancers, including that of the prostate. Laboratory and clinical studies have demonstrated that green tea components, specifically the green tea catechin (GTC) epigallocatechin gallate, can induce apoptosis, suppress progression, and inhibit invasion and metastasis of prostate cancer. Multiple mechanisms are involved in the chemoprevention of prostate cancer with GTCs; understanding and refining models of fundamental molecular pathways by which GTCs modulate prostate carcinogenesis is essential to apply the utilization of green tea for the chemoprevention of prostate cancer in clinical settings. The objective of this article is to review and summarize the most current literature focusing on the major mechanisms of GTC chemopreventative action on prostate cancer from laboratory, in vitro, and in vivo studies, and clinical chemoprevention trials.

Associations Between Body Size and Serum Estradiol and Sex Hormone-Binding Globulin Levels in Premenopausal African American Women

CONTEXT African American (AA) women have the highest rates of premenopausal breast cancer; however, it is unclear whether body size contributes to the hormonal patterns potentially associated with increased breast cancer risk in these women. OBJECTIVE To characterize the association between body size and serum levels of estradiol and sex hormone-binding globulin (SHBG) levels in a sample of premenopausal AA women. DESIGN A total of 164 premenopausal AA women who were not pregnant or breastfeeding were recruited for this study. Serum samples were collected during the early follicular phase, and trained staff collected body size measurements. Multiple linear regression models were performed to assess potential associations. MAIN OUTCOME MEASURES Serum estradiol and SHBG levels. RESULTS Many (81%) of the women enrolled were overweight or obese. Both waist-to-hip ratio (WHR) (β = 2.68, P = .008) and waist circumference (WC) (β = 2.02, P = .046) were positively associated with higher levels of estradiol. All measures of body was significantly and inversely associated with SHBG levels (all P < .05). CONCLUSIONS Premenopausal AA women with higher WHR or larger WC may have higher levels of estradiol and lower levels of SHBG. Thus, WHR or WC may be better indicators for assessing hormonal patterns implicated in breast cancer pathogenesis in these women.

Safety and Chemopreventive Effect of Polyphenon E in Preventing Early and Metastatic Progression of Prostate Cancer in TRAMP Mice

Prostate cancer treatment is often accompanied by untoward side effects. Therefore, chemoprevention to reduce the risk and inhibit the progression of prostate cancer may be an effective approach to reducing disease burden. We investigated the safety and efficacy of Polyphenon E, a green tea extract, in reducing the progression of prostate cancer in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. A total of 119 male TRAMP and 119 C57BL/6J mice were treated orally with one of 3 doses of Polyphenon E (200, 500, and 1,000 mg/kg/day) in drinking water ad libitum replicating human achievable doses. Baseline assessments were performed before treatments. Safety and efficacy assessments during treatments were performed when mice were 12, 22, and 32 weeks old. The number and size of tumors in treated TRAMP mice were significantly decreased compared with untreated animals. In untreated 32 weeks old TRAMP mice, prostate carcinoma metastasis to distant sites was observed in 100% of mice (8/8), compared with 13% of mice (2/16) treated with high-dose Polyphenon E during the same period. Furthermore, Polyphenon E treatment significantly inhibited metastasis in TRAMP mice in a dose-dependent manner (P = 0.0003). Long-term (32 weeks) treatment with Polyphenon E was safe and well tolerated with no evidence of toxicity in C57BL/6J mice. Polyphenon E is an effective chemopreventive agent in preventing the progression of prostate cancer to metastasis in TRAMP mice. Polyphenon E showed no toxicity in these mouse models. Our findings provide additional evidence for the safety and chemopreventive effect of Polyphenon E in preventing metastatic progression of prostate cancer. Cancer Prev Res; 7(4); 435–44. ©2014 AACR.

A Case Study Approach to Train Early-Stage Investigators in Transdisciplinary Research

Emily C. Benesh, PhD∗1,a−b; Laura E. Lamb, PhD∗2,c−d; Shahnjayla K. Connors, PhD, MPH, CPH; Grant W. Farmer, PhD, MPH, MA; Katherine C. Fuh, MD, PhD ; Jean Hunleth, PhD, MPH; Katherine L. Montgomery, PhD, MSSW; Alex T. Ramsey, PhD, MA; Kelle H. Moley, MD; Graham A. Colditz, MD, DrPH; Sarah J. Gehlert, PhD4,5,7,a,e,h,i∗∗ Divison of Basic Sciences Research, Department of Obstetrics and Gynecology Washington University School of Medicine in St. Louis, Saint Louis, MO; Beaumont Health Systems Research Institute, Royal Oak, MI; The Genome Institute at Washington University School of Medicine in St. Louis, Saint Louis, MO; Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine in St. Louis, Saint Louis, MO; Divison of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine in Saint Louis, Saint Louis, MO; George Warren Brown School of Social Work, Washington University in St. Louis, Saint Louis, MO; Siteman Cancer Center, Washington University School of Medicine in St. Louis, Email: sgehlert@wustl.edu.

Abstract A86: Identifying system-level barriers to breast cancer treatment which lead to health disparities for vulnerable communities: A qualitative approach

Purpose of Study: This study is a part of a larger community-based participatory research (CBPR) project to decrease African-American and white breast cancer mortality disparities in Saint Louis, Missouri. Specifically, we explore the course of breast cancer treatment for a group of primarily low-income African American women living in North St. Louis at the time of diagnosis to identify factors that may contribute to discontinuation of breast cancer treatment. Methods: For this study, funded by Susan G Komen for the Cure, two sources of data (semi-structured interviews and medical record extraction) were explored to fully capture reasons for completion or discontinuation of prescribed treatment. We analyze data for 85 women for whom both sources of data were available and were treated at a large teaching hospital. Inclusionary criteria were at least 18 years of age and diagnosed with breast cancer while living in eight zip codes of North St. Louis, the latter chosen because they have been identified as part of a cluster of late stage diagnosis. Women were recruited via letters from the Missouri Cancer Registry and flyers prepared and distributed by community partner organizations. The approach had two components: (1) individual in-home interviews were conducted based on narrative theory to collect treatment history in the women9s own voices; and (2) review of electronic medical records of the women to determine what supports were offered, and what treatment prescribed, to them. Patient narratives were coded using NVivo 10.0 and themes derived using grounded theory. Results: Two themes were most prevalent among the narratives from the women interviewed that suggest reasons why African-American women in the study may not have complete treatment prescribed. First, women did not connect radiation therapy with survival in the same way that they did surgery and chemotherapy. Rather, they described it in terms that made it seem optional, like breast reconstruction. Second, while women seemed to have been supported in terms of obstacles to treatment near the time of surgery, they reported no such services after receiving chemotherapy. Chart review revealed that patient navigation tapers off after surgery, with only one navigator employed by medical oncology and none in radiation oncology. Conclusions and Implications: Women describing radiation therapy as an optional treatment reflects a misunderstanding of the importance of radiation therapy in breast cancer survival. Relatedly, having navigators associated with each service (surgical, medical, and radiation oncology) who communicate regularly with one another may help to ensure that women complete prescribed treatment, thus decreasing the African American and white breast cancer mortality disparity in St. Louis. Further study is suggested to determine if these findings persist in other locations. Citation Format: Lailea Noel, Melody Goodman, Shahnjayla K. Connors, Dwayne Butler, Ron McMullen, Cheryl Oliver, Isaac McCullough, Sarah Gehlert. Identifying system-level barriers to breast cancer treatment which lead to health disparities for vulnerable communities: A qualitative approach. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr A86. doi:10.1158/1538-7755.DISP13-A86

Abstract C49: Treatment delay among African American women in St. Louis, Missouri

Introduction: Breast cancer mortality rates in the metropolitan St. Louis area are higher than those of Missouri as a whole or the United States. Similar to national trends, African American women in St. Louis have higher mortality rates than their Caucasian counterparts. Differences in the receipt of timely breast cancer treatment have been posited to be a factor that contributes to the disparity in breast cancer mortality between African American and Caucasian women. A cluster of late-stage breast cancer diagnoses has been identified in women living in North St. Louis, a predominantly African American area of St. Louis. Previous studies have shown that significant breast cancer diagnosis delays were occurring in woman referred from the St. Louis Safety Net System. The current study was carried out to examine treatment delay in a cohort of African American women diagnosed with breast cancer in North St. Louis between 2000 and 2008. Methods: Data were obtained from medical record extractions for 85 women who participated in a study funded by Susan G. Komen for the Cure that also included qualitative semi-structured interviews to determine breast cancer treatment histories. Medical records were examined for information about the type, timing, and sequence of breast cancer treatment. All of the women were treated within a local urban academic medical system. Treatment delay was calculated from the date of biopsy to the initiation of treatment and chi square tests were used to examine bivariate associations between demographic or clinical factors and treatment delay. Results: The median treatment delay was 26.5 days; 12.2% of the women had treatment delay over 60 days. This percentage is below the National Breast and Cervical Early Detection Program benchmark which states that no more than 20% of women should have a treatment delay of over 60 days. There were no statistically significant associations between demographic or clinical factors and treatment delay. Discussion: North St. Louis has the most concerning health and community indicators in the St. Louis area. In spite of the fact that this cohort of women resided in North St. Louis at diagnosis, there was no evidence of breast cancer treatment delay. These findings suggest that it is possible to treat racial and ethnic minority women with breast cancer without treatment delay, regardless of demographic factors. Delay in breast cancer treatment affects patient survival and is a vital area of breast cancer treatment research. More multidisciplinary approaches are needed to fully understand the many factors that contribute to breast cancer treatment delay so that interventions can be developed to improve outcomes in all breast cancer patients, particularly for African American women who suffer higher mortality rates despite lower incidence rates. Citation Format: Shahnjayla K. Connors, Melody Goodman, Neeraja Chavakula, Lailea Noel, Sarah Gehlert. Treatment delay among African American women in St. Louis, Missouri. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr C49. doi:10.1158/1538-7755.DISP13-C49

Abstract 616: A cumulative molecular model for the mechanisms of green tea catechins in the chemoprevention of prostate cancer

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Background: Prostate cancer (CaP) is the most commonly diagnosed cancer in men. Its long latency, slow progression, and high incidence rates make it ideal for targeting chemoprevention therapies. Studies suggest that green tea may be suitable candidate for CaP chemoprevention. The green tea catechin (GTC) chemopreventive mechanisms against CaP cells, however, are not completely clear. Understanding and refining models of the fundamental molecular pathways by which GTCs modulate prostate carcinogenesis is essential to most appropriately utilize green tea for CaP prevention in clinical settings. Objective: The objective of the study was to review the current literature and develop a model that attempts to recreate the molecular mechanisms and pathways by which GTCs modulate prostate carcinogenesis. Methods: Laboratory studies, clinical studies, and clinical trials focused on GTC chemoprevention of CaP were critically analyzed and reviewed for mechanisms of GTC chemoprevention. The most prevalent mechanisms were combined into a multi-mechanistic model that attempts to recreate the cumulative events that occur as GTCs exert anti-cancer activity on prostate cancer cells and tissues. Results: GTCs exert anti-cancer actions on CaP cells and tissue through six major mechanisms: proteasome inhibition, cell cycle arrest, inhibition of cell proliferation, induction of apoptosis, suppression of carcinogenesis/progression, and inhibition of metastasis. We have proposed a novel model in which GTCs exert chemopreventive effects on CaP though these six major mechanisms that work simultaneously and dependently, largely driven by proteasome inhibition-induced regulation of the NFκB pathway. The cumulative effect of these mechanisms ultimately leads to the inhibition of CaP cell growth, progression, and metastasis. Conclusions: Several mechanisms of GTC chemopreventive activity on CaP cells and tissues have been identified in laboratory and clinical studies. Although GTCs act through distinct cell cycle regulative pathways, the cumulative chemopreventative effect appears to be attributed to their well-coordinated ensemble, rather than a single pathway. Additionally, transitioning to the use of standardized GTC preparations may more accurately reflect human tea consumption, deliver the maximum amount of GTCs, and allow for more generalizable results in epidemiological, laboratory, and clinical studies. We are currently testing and refining our novel cumulative model to fully elucidate the complex mechanism of GTC chemoprevention of prostate cancer in its entirety. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 616. doi:1538-7445.AM2012-616