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EDRI Federal Project Inventory:
70714-01 P450 Link Between Hormonal and Chemical Carcinogenesis
- Sponsor Organization: NIH/NCI
- Project Title: 70714-01 P450 LINK BETWEEN HORMONAL AND CHEMICAL CARCINOGENESIS
- Project Focus: EXPOSURE ASSESSMENT
- Description: Studies of the role of estrogens (Es) in the etiology of breast
cancer have focused on their receptor- mediatedactions as
mitogens. However, such actions of Es can not fully explain either
laboratory or epidemiological data.However, Es can undergo P450-
mediated metabolic activation to generate electrophilic species
which are knowninitiators of carcinogenesis. This concept has evolved
from studies of the biogenesis and characteristics of 2- and 4-
hydroxylated catechol metabolites of Es (2- and 4-OH-CEs) which may
damage DNA via oxygen free radicals generatedby redox cycling of CEs
or by causing depurinating adducts via their quinone metabolites. The
mechanisms involved areanalogous to those by which xenobiotic
procarcinogens undergo P450-mediated metabolic activation to
proximalcarcinogens. The overall hypothesis states that 2- and 4-OH-
CEs generated in the gland, in particular 4-OH-CEs, are important
determinants of P450- mediated Es role in carcinogenesis, in
particular, in the early initiating stages of thedisease. According to
this postulate P450s which can generate CEs and their quinone
derivatives and support redoxcycling of CEs provide an interface
between chemical and hormonal carcinogenesis, since these forms of
P450 Es areinducible by xenobiotics. The relevance of this postulate
to breast cancer is supported by recent cytochemical findingsthat all
of the forms of P450 required for such a mechanism are expressed in
ductal epithelial cells in the normal humanbreast. The forms of P450
identified include P45O1A1 and 3A4 which can catalyze formation of 2-
OH-CEs and redoxcycling of CEs, as well as recently identified P4501B1
which, in its dioxin-inducible form in MCF-7 cells, is an E-4-
hydroxylase. This is the first P450 known which generates 4- OH-CEs
preferentially, the class of CEs which theinvestigator proposes may
play a special role in carcinogenesis since they are potent long
acting Es and may be lessreadily inactivated than 2-OH-CEs. The
specific goal of proposed experiments is to determine if the
constitutive form ofP4501B1 expressed in human mammary gland, like
that induced by ioxins in cultured cells, is an E-4-hydroxylase
andthe extent to which its sequence conforms to that induced by
dioxin. Probes for screening cDNA libraries from humanbreast
parenchyma will be obtained by polymerase chain reaction applied to
reverse transcripts (RT/PCR) to RNAprepared from the same tissue and
using asymmetrical primers based on the sequences used to identified
P4501B1 inhuman breast by in situ hybridization.
- References:
- Category: METHODS
- Subcategory: BASIC RESEARCH
- Keywords for Experimental System/Species: HUMAN, LABORATORY STUDY, IN VITRO
- Keywords for Experimental Endpoints: CARCINOGENESIS, HORMONAL MEASURES, XENOBIOTIC METABOLISM,
CYTOCHROME P450
- Chemical Agents: DIOXIN
- Performing Institution: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
- Contact: CONTRACT PERSON: ELAINE C. LEE; BUILDING 31; 11A21; NATIONAL CANCER
INSTITUTE, NIH,BETHESDA, MD 20892-2590; 301-496-5515;
LEEE@OD.NCI.NIH.GOV
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