ABSTRACT
Cancer is one of the leading causes of death worldwide. The global cancer burden (GCB) is expected to rise significantly and will disproportionately affect the less developed world (LDW). The aim of this review is to analyze the trends in GCB and describe the types, estimates, and causes of new cancer cases. The challenges and strategies associated with tackling this rising GCB are described in which surgeons can play a vital role.
Subject(s)
Cost of Illness , Global Health , Medical Oncology , Neoplasms , Physician's Role , Specialties, Surgical , Developing Countries , Global Health/statistics & numerical data , Global Health/trends , Health Promotion , Health Services Accessibility , Healthcare Disparities , Humans , Neoplasms/epidemiology , Neoplasms/etiology , Neoplasms/surgeryABSTRACT
Estrogens are a known risk factor for breast cancer. Studies indicate that initiation of breast cancer may occur by metabolism of estrogens to form abnormally high levels of catechol estrogen-3,4-quinones, which can then react with DNA to form depurinating adducts and, subsequently, induce mutations that lead to cancer. Among the key enzymes metabolizing estrogens are two activating enzymes: cytochrome P450 (CYP)19 (aromatase), which converts androgens to estrogens, and CYP1B1, which converts estrogens predominantly to the 4-catechol estrogens that are further oxidized to catechol estrogen-3,4-quinones. Formation of the quinones is prevented by methylation of the 4-catechol estrogens by the enzyme, catechol-O-methyltransferase (COMT). In addition, catechol estrogen quinones can be reduced back to catechol estrogens by NADPH quinone oxidoreductase 1 (NQO1) and/or are coupled with glutathione, preventing reaction with DNA. Thus, COMT and NQO1 are key deactivating enzymes. In this initial study, we examined whether the expression of these four critical estrogen activating/deactivating enzymes is altered in breast cancer. Control breast tissue was obtained from four women who underwent reduction mammoplasty. Breast tissues from five women with breast carcinoma, who underwent mastectomy, were used as cases. The level of expression of CYP19, CYP1B1, COMT and NQO1 mRNAs was quantified from total RNA using a real time RT-PCR method in an ABI PRISM 7700 sequence detection system. The control breast tissues showed lower expression of the activating enzymes, CYP19 and CYP1B1, and higher expression of the deactivating enzymes, COMT and NQO1, compared to the cases. In the cases, the reverse pattern was observed: greater expression of activating enzymes and lower expression of deactivating enzymes. Thus, in women with breast cancer, estrogen metabolism may be related to altered expression of multiple genes. These unbalances appear to be instrumental in causing excessive formation of catechol estrogen quinones that, by reacting with DNA, initiate the series of events leading to breast cancer.
Subject(s)
Breast Neoplasms/metabolism , Carcinoma/metabolism , Estrogens/metabolism , Gene Expression Regulation, Neoplastic , Adipose Tissue/metabolism , Adult , Aged , Aromatase/metabolism , Aryl Hydrocarbon Hydroxylases/metabolism , Breast/metabolism , Breast Neoplasms/enzymology , Breast Neoplasms/pathology , Carcinoma/enzymology , Catechol O-Methyltransferase/metabolism , Cytochrome P-450 CYP1B1 , DNA/chemistry , DNA/metabolism , Female , Humans , Middle Aged , Models, Chemical , Mutation , NAD(P)H Dehydrogenase (Quinone)/metabolism , Oxygen/chemistry , RNA/chemistry , RNA/metabolism , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Risk Factors , Time FactorsABSTRACT
Exposure to estrogens has been associated with an increased risk of developing breast cancer. Breast biopsy tissues from 49 women without breast cancer (controls) and 28 with breast carcinoma (cases) were analyzed by HPLC with electrochemical detection for 31 estrogen metabolites and catechol estrogen quinone-glutathione conjugates. The levels of estrone and estradiol were higher in cases. More 2-catechol estrogen (CE) than 4-CE was observed in controls, but the 4-CE were three times higher than 2-CE in cases. In addition, the 4-CE were nearly four times higher in cases than in controls. Less O-methylation was observed for the CE in cases. The level of catechol estrogen quinone conjugates in cases was three times that in controls, suggesting in the cases a higher probability for the quinones to react with DNA and generate mutations that may initiate cancer. The levels of 4-CE and quinone conjugates were highly significant predictors of breast cancer. These results suggest that some catechol estrogen metabolites and conjugates could serve as biomarkers to predict risk of breast cancer.
