Research Goals
Section Chief
Section Members
  Gong, Min
  Knight, Laundette
  Qiu, Cunping
  Shan, Liang
  Sinha, Ranjana
  Yoon, Hae-Seong
  Yu, Minshu
Training
Research Results
References
 

Research Results


The Food-Derived Heterocyclic Amines
The food-derived heterocyclic amines (HCAs) comprise a family of mutagenic/carcinogenic compounds found in a variety of meats cooked by ordinary household methods. These compounds were first detected as mutagenic components in well-done portions of broiled fish and beef in the late 1970's and early 1980's. Today approximately twenty HCAs have been identified and several including 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) are recognized as dietary carcinogens having a potentially significant impact on the etiology of human cancer (see Reference 1 for review, Reference 2). The heterocyclic amines belong to the aromatic amine class of carcinogens that have been known for many years to be involved in the etiology of specific human cancers. (conference website http://www.palladianpartners.com/amineconference).

Structure of PhIP

Structure of PhIP, the major known carcinogenic heterocyclic amine in the human diet.
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Breast Cancer and Dietary Heterocyclic Amines
Breast cancer is a major public health problem among women living in the United States, yet the etiology of this disease is still poorly understood. Diet and lifestyle are recognized as important factors in the incidence of breast cancer (see Reference 1 for review). Breast cancer incidence rates are associated with specific dietary habits. The wide variation in breast cancer incidence rates among individuals living in different countries is consistent with the possibility that specific carcinogens in the diet and environment contribute to the etiology of breast cancer. This laboratory has set-up an model system demonstrating the rapid induction of mammary gland cancer with PhIP (Reference 5). Findings from our laboratory and elsewhere showing that several HCAs derived from cooked meat are mammary gland carcinogens in rats have provided support for the notion that HCAs may be involved in the etiology of certain human breast cancers.

Dietary factors, such as the consumption of well-done cooked meat, may impact breast cancer risk.
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Mechanisms of Mammary Gland Carcinogenesis of PhIP
PhIP is currently recognized as the major HCA in the human diet. This laboratory currently seeks to define the critical events in the process of PhIP-induced mammary gland carcinogenesis in animal models and in vitro assays using rodent and human mammary tissue and epithelial cells. In addition to studies on metabolic activation, carcinogen disposition, and DNA adduct formation, this laboratory seek to better understand the cell biology of the mammary gland as a means to elucidate the factors that confers susceptibility to chemical carcinogens. Studies further address genomic alterations induced by PhIP during mammary gland carcinogenesis. For example, highly recurrent regions of allelic imbalance, including loss of heterozygosity, indicative of sites of putative tumor suppressor genes, have been recently detected in PhIP-induced rat mammary carcinomas (Reference 6).
Terminal End Buds
Wholemount view of rat mammary gland terminal end buds. Terminal end buds appear to be the structures that are most susceptible to malignant transformation by PhIP.

Histological view of normal terminal end buds (upper panel) and a microscopic carcinoma in a rat mammary gland.

PhIP-induced rat mammary carcinomas were shown to harbor allelic imbalance
(Yu et al., Molecular Carcinogenesis 27: 76-83, 2000) Abstract of this publication (opens in new browser window)
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Metabolism and DNA Adduct Formation
Metabolic processing and DNA adduct formation is critical for HCA carcinogenesis. This laboratory section investigates HCA-DNA adduct formation, metabolic processing, and DNA adduct-induced mutagenesis with current focus on the mammary gland as a target site. Our research has demonstrated the importance of specific pathways of metabolic activation in HCA-DNA adduct formation and carcinogenesis (Reference 2).

Structure of the major PhIP-DNA adduct (N-(deoxyguanosin-8-yl)-PhIP) found in the mammary gland of rats that succumb to the carcinogenic effects of PhIP (Snyderwine et al., Carcinogenesis 19: 1209-1215, 1998 - Abstract opens in new browser window)
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