Knapp J.S., Cabrera W.L. Metabolomics: Metabolites, Metabonomics, and Analytical Technologies
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The Role of Specific Estrogen Metabolites… 247
The Breast of Women with Breast Carcinoma
A study of breast tissue from women with and without breast cancer provides key
evidence in support of the concept of estrogen homeostasis [17]. In fact, relative imbalances
in estrogen homeostasis were observed in analysis of women with breast cancer (Figure 2).
Levels of E
1
and E
2
in women with carcinoma were higher than in controls. In women
without cancer, a larger amount of 2-OHE
1
(E
2
) than 4-OHE
1
(E
2
) was observed. In women
with carcinoma, the 4-OHE
1
(E
2
) were three times more abundant than the 2-OHE
1
(E
2
). The
4-OHE
1
(E
2
) were also four times higher than in women without cancer. Furthermore, a lower
level of methylation was observed for the catechol estrogens in cancer cases vs the controls.
Levels of E
1
(E
2
)-Q conjugates in women with cancer were three times those in controls,
suggesting a larger probability for the E
1
(E
2
)-Q to react with DNA in the breast tissue of
women with carcinoma. Levels of 4-OHE
1
(E
2
) (p<0.01) and quinone conjugates (p<0.003)
appear to be highly significant predictors of breast cancer [17]. Further support for this
concept is provided by detection of the 4-OHE
2
-1-N3Ade adduct in non-tumor breast tissue
from a woman with breast carcinoma at a level 30 times higher than in breast tissue from a
woman without breast cancer [38].
In summary, it appears from these animal and human studies that the formation of E
1
(E
2
)-
3,4-Q from catechol estrogens is the result of an imbalance of one or more enzymes involved
in the maintenance of estrogen homeostasis.
Estrogen-Induced Mutations and Cell Transformation
Mutations are induced in the Harvey (H)-ras oncogene in the skin of female SENCAR
mice following topical treatment with E
2
-3,4-Q [9]. Mutations are also induced in the H-ras
oncogene in the mammary gland of female ACI rats [28], which develop mammary tumors
when implanted with E
2
[39]. These studies demonstrate that E
2
-3,4-Q is mutagenic. This
mutagenicity has been correlated with formation of depurinating DNA adducts, in particular
the rapidly depurinating 4-OHE
2
-1-N3Ade [9,19,28].
Figure 2. Analysis of estrogen metabolites and conjugates in human breast tissue from women with and
without breast cancer. Controls are benign fatty breast tissue and benign fibrocystic changes. Quinone
conjugates are 4-OHE
1
(E
2
)-2-NAcCys, 4-OHE
1
(E
2
)-2-Cys, 2-OHE
1
(E
2
)-(1+4)-NAcCys and 2-
OHE
1
(E
2
)-(1+4)-Cys. *Statistically significant differences were determined using the Wilcoxon rank
sum test, p<0.01 [4-OHE
1
(E
2
)] and p<0.003 (quinone conjugates).
Eleanor G. Rogan and Ercole L. Cavalieri 248
Both E
2
and the catechol estrogen 4-OHE
2
also induce cell transformation in the human
breast epithelial MCF-10F cell line [40,41]. It is significant to note that the neoplastic
transformation of MCF-10F cells by E
2
or 4-OHE
2
is not blocked by the antiestrogen ICI 182-
780, indicating that this event is occurring by a non-receptor mediated process [42]. These
data suggest that the initiating step leading to cell transformation derives from the DNA
damage produced by E
2
-3,4-Q, the oxidative metabolite of 4-OHE
2
.
Conclusions
A growing body of evidence from studies with laboratory animals, cultured cells and
human tissues supports the hypothesis that estrogens can initiate cancer by formation of
specific DNA adducts leading to mutations in critical genes. The E
1
(E
2
)-3,4-Q are the
predominant estrogen metabolites that react with DNA to form depurinating N7Gua and
N3Ade adducts, generating apurinic sites and subsequent mutations. This approach to
studying estrogen-induced cancer not only guides the study of the role of estrogens in
initiating cancer, but also provides candidate biomarkers that may be used to determine risk
of developing breast, prostate or other types of cancer. These studies also suggest possible
strategies to prevent the development of cancer.
Acknowledgments
Preparation of this article was supported by U.S. Public Health Service grants P01
CA49210 and R01 CA49917 from the National Cancer Institute. Core support in the Eppley
Institute is provided by grant P30 CA36727 from the National Cancer Institute.
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AACR, 45, 11.
INDEX
A
absorption, 33, 204
accessibility, 104, 191, 211
acclimatization, 176
accuracy, ix, 100, 122, 131, 136, 138, 141, 144, 157,
158, 161, 191, 224, 225
acetone, 130
acetonitrile, 127, 130, 132, 136
acid, 80, 89, 92, 106, 109, 113, 129, 131, 134, 148,
149, 156, 157, 167, 168, 185, 192, 197, 198, 204,
236
acidity, 114
acrylic acid, 156
active site, 190
adaptation, 108, 167, 168, 170, 172, 176, 187, 189,
193, 194
adaptations, 119
adenocarcinoma, 109, 142, 249, 250
adenosine, 236
adhesion, 99, 101
adipose, 142
adipose tissue, 142
advantages, 22, 91, 108, 123, 142, 210
aerosols, 164
AFM, 159, 160
agglomeration, 59, 60
aggregation, 51, 57, 59
aggressiveness, 88, 92
agriculture, 170, 175, 180, 182
Albania, 215
alcohols, 126, 131, 149, 160
aldehydes, 160
algorithm, 53, 57, 58, 59, 85, 189, 220, 223, 226,
227, 228, 241
alkylation, 131
alternative hypothesis, 108
amines, 131
amino acids, 126, 149, 152, 166, 170, 193, 236
ammonium, 166
anabolism, 234
aneuploidy, 94, 113
annotation, 81, 124, 157, 235
antibiotic, 195
anti-cancer, ix, 88
antigen, 113
antimicrobial therapy, 196
antioxidant, 92
antisense, 111
apoptosis, viii, 87, 89, 99, 102, 108, 109, 113, 117
Arabidopsis thaliana, 152, 155, 166, 168, 169, 170,
172, 173, 174, 176, 177, 180
architecture, 98, 99, 101, 105, 107, 205
artificial intelligence, 217
ascites, 113
assessment, x, 119, 160, 163, 169, 179, 204, 205,
212, 213, 233
assets, 136
assimilation, 168
asymmetry, 23
ataxia, 96
atmospheric pressure, 141, 159, 160
atoms, 225
ATP, 88, 92, 93, 96, 108, 116, 236
automation, 206
B
BAC, 196
bacteria, 129, 151, 185, 186, 187, 188, 189, 190,
193, 194, 195, 197
bacterial strains, 198
bacteriocins, 187, 194
bacterium, 185, 193, 199
banks, 191
basic research, 165
bending, 103
benign, 95, 101, 247
beverages, 191
bias, 23, 62, 128, 184
bile, 147
bile acids, 147
biocatalysts, 182, 192
biochemistry, 99, 102, 129, 165, 202, 232, 234
Index
254
bioconversion, 198
biodegradation, 193, 198
biodiversity, 196
biogeography, 164
bioinformatics, 144, 182, 204, 210, 232, 233, 234,
238
biological activity, 212
biological processes, x, 119, 201
biological responses, xi, 229
biological sciences, 208
biological systems, 3, 118, 123, 136, 154, 215, 216,
217, 237
biomarkers, 80, 81, 122, 145, 146, 151, 165, 169,
185, 206, 211, 233, 248, 249
biomass, 106, 165, 170, 176, 187, 190, 191, 194, 198
biomedical applications, 151
biomonitoring, 187
biosphere, x, 181
biosynthesis, 2, 33, 35, 62, 92, 171, 177, 250
biosynthetic pathways, 108
biotechnology, xii, 149, 190, 191, 195, 199, 230
biotic, 164, 169, 172, 173, 174, 233
blood plasma, 154
blood supply, 98
body fluid, 129, 146, 206
bonds, 150
bone, 189
brain, 91, 140, 142, 159
breast cancer, viii, 88, 93, 102, 103, 104, 105, 108,
112, 233, 240, 245, 247, 248, 249, 250
breast carcinoma, 114, 247
Britain, ix, 82, 163, 178
browsing, 193
buffalo, 191, 196, 197, 198
building blocks, 203, 216
C
cadmium, 146, 167, 174
caecum, 188, 197
calculus, 2, 26, 29, 68, 74
cancer, vii, viii, xii, 87, 88, 89, 91, 92, 93, 94, 95, 96,
97, 98, 99, 100, 101, 102, 103, 104, 105, 107, 108,
109, 110, 112, 113, 114, 115, 116, 117, 118, 119,
129, 151, 152, 232, 233, 240, 243, 244, 247, 248,
249
cancer cells, vii, viii, 87, 88, 89, 92, 93, 94, 96, 97,
98, 101, 103, 104, 108, 109, 110, 112, 114, 116,
118, 119
cancer progression, 108, 117
candidates, 193
capillary, 125, 127, 128, 129, 135, 146, 147, 149,
150, 155, 156, 157
carbohydrate, 111, 147, 166, 188, 198
carbohydrate metabolism, 111
carbohydrates, 152, 164, 166
carbon, 93, 96, 109, 113, 115, 150, 164, 170, 176,
177, 179, 236
carbon dioxide, 88, 113, 164, 167, 170, 174, 177,
178, 236
carbonyl groups, 131
carcinogen, 248
carcinogenesis, 95, 96, 107, 114, 116, 205, 246, 250
carcinogenicity, xii, 243, 244
carcinoma, 80, 109, 113, 115, 129, 247, 249, 251
carotenoids, 158
cartilage, 103
case study, 177
casein, 107
catabolism, 234
cation, 26, 126, 127, 128
cattle, 188, 192, 194
causation, 88
CEC, 207
cecum, 196
cell culture, 107, 157, 174, 202
cell cycle, 93, 95, 97, 108
cell death, 89, 115
cell fate, 97, 99, 102
cell invasion, 119
cell line, 92, 93, 96, 102, 104, 105, 107, 109, 112,
248
cell lines, 92, 93, 96, 112
cell metabolism, 91, 97, 106, 109, 112
cell surface, 99
cellulose, 199
cement, 97
cerebrospinal fluid, 231
cervical cancer, 112
chemical properties, 123
chemical reactions, 11, 89, 216, 226, 231, 234, 236
chemometrics, 166, 171, 174
chicken, 142, 197
China, 161, 198
chloroform, 130
cholesterol, 93, 113
chondrocyte, 103, 119
chromatograms, ix, 122, 124, 125, 142
chromatographic technique, 210
chromatography, ix, 81, 90, 121, 123, 124, 125, 134,
136, 142, 144, 147, 148, 149, 150, 151, 152, 153,
155, 156, 158, 160, 206, 207, 249
chromosome, 195, 198
circadian rhythm, 170
circadian rhythms, 170
circulation, 204
class, 90, 131, 164, 171, 206, 226
cleaning, 140
climate, 166, 168, 176, 179
climate change, 166, 168, 176, 179
clinical oncology, 109
clinical trials, 211, 240
clone, 186, 195
cloning, 113, 183, 184, 185, 189, 191, 197, 199
closure, 102
cluster analysis, 50, 51, 52, 54, 60, 80, 213
Index
255
clustering, 51, 52, 53, 57, 58, 60, 61, 81, 82, 83, 186,
211, 235, 238
clusters, 51, 52, 53, 57, 58, 59, 60, 61, 62, 81, 237
coding, 230
codon, 189
collagen, 103
colon, 80, 117
colon cancer, 117
commodity, 180
community, 143, 146, 167, 183, 184, 185, 191, 199
compatibility, 132
competition, 18, 35, 133, 155, 164, 169, 170, 176
complement, xi, 91, 123, 154, 208, 229
complex interactions, 190, 216
complexity, vii, xi, 1, 3, 7, 37, 38, 52, 85, 100, 101,
102, 103, 116, 118, 126, 131, 154, 185, 188, 203,
215, 216, 220
compliance, 99
composition, 103, 111, 123, 170, 202, 205, 210
compost, 182, 183
compound identification, vii, 126
compounds, ix, 35, 83, 85, 88, 89, 90, 91, 96, 104,
126, 127, 128, 129, 130, 131, 133, 136, 138, 140,
141, 142, 143, 148, 149, 150, 164, 165, 166, 168,
169, 170, 171, 178, 193, 202, 203, 204, 207, 208,
212, 221, 223, 231, 232, 236
comprehension, x, 89, 181, 216
compression, 99
computation, 8, 22, 30, 31, 32, 34, 41, 51, 55, 57, 67,
75, 76, 77, 79
computing, 69
conductivity, 133
configuration, 101, 104, 107
conformational analysis, 207
conjugation, 244, 246, 249
connective tissue, 118, 213
connectivity, 3, 8, 80, 81, 85, 90
consensus, 108, 146
consent, 125
conservation, 36
consulting, 30
consumption, viii, 87, 93, 96, 105, 156, 207
consumption rates, 93
contingency, 72
continuous data, 53
control group, 105
convergence, 14, 97
coronary heart disease, 145
correlation, vii, viii, 1, 2, 3, 8, 16, 17, 18, 19, 21, 22,
23, 24, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36,
37, 49, 50, 53, 65, 66, 67, 82, 88, 93, 98, 103, 105,
106, 202
correlation analysis, vii, 1, 19, 21, 22, 30
correlation coefficient, 21, 23, 24, 26, 28, 29, 53, 105
correlations, vii, 1, 2, 8, 16, 24, 27, 28, 29, 30, 31,
32, 33, 34, 35, 36, 37, 38, 47, 50, 80, 84, 103, 234
cost, 101, 135, 174, 207, 210
critical value, 30
crops, 176, 177, 205
cues, viii, 88, 98, 190
cultivation, 185, 196
culture, x, 92, 95, 97, 105, 149, 182, 183, 184, 187
culture conditions, 97, 182, 187
culture media, 182
current limit, 131
cytochrome, 112, 244, 249, 250
cytoskeleton, 99, 100
D
data analysis, 20, 80, 138, 142, 160, 184, 211, 213,
238
data mining, 143, 217, 227
data processing, 143, 210
data set, 105, 124, 143, 189, 233
data structure, 69
database, xi, 67, 74, 78, 84, 131, 154, 161, 186, 208,
210, 218, 229, 230, 231, 232, 239
datasets, vii, 1, 2, 7, 29, 30, 35, 47, 54, 74, 224, 226,
237
decomposition, 39, 40, 41, 150, 164, 167, 237
deconvolution, 142
defence, 92, 165, 170, 176
deficiencies, 93, 96, 165, 210
deficiency, 96, 165, 166, 202
deformability, 117
degenerate, 82
degradation, 91, 92, 108, 111, 182, 185, 193, 197,
198, 203
deposition, 96, 165, 175
deregulation, 80, 108
derivatives, viii, 2, 13, 85, 110, 131, 150, 244
desorption, ix, 122, 128, 139, 140, 150, 158, 159,
160
detachment, 101
detection, ix, 65, 71, 80, 81, 83, 115, 121, 122, 126,
131, 133, 135, 136, 137, 139, 142, 149, 150, 152,
155, 157, 159, 185, 186, 196, 206, 207, 211, 235,
247
detoxification, 182, 190, 191
developing countries, 194
deviation, 31, 107
diabetes, 96, 115, 129, 149
diabetic patients, 96, 115
diagnosis, 100, 102, 145, 146, 148, 149, 204, 212,
233
diagnostic criteria, 2
diagnostic markers, 210
diet, 159, 202, 203, 209, 210, 230
dietary fat, 113
dietary fiber, 195
dietary habits, 96
diffusion, 98, 112
digestion, 190, 195
disadvantages, 133, 135, 142
discordance, 63
discriminant analysis, 154, 171
Index
256
discrimination, 158, 175, 178
dispersion, 21, 22, 23, 28, 33, 47
distinctness, 61, 62
distortion, 99, 101
disturbances, 206
divergence, 14
diversification, 84, 106, 180
diversity, viii, x, 20, 50, 62, 67, 78, 83, 88, 95, 98,
114, 133, 171, 177, 179, 181, 182, 184, 185, 189,
194, 196, 197, 198
DNA, x, xii, 88, 92, 168, 183, 184, 185, 186, 187,
189, 191, 192, 195, 197, 199, 201, 213, 243, 244,
245, 246, 247, 248, 249, 251
DNA polymerase, 183
DNA repair, 189
down-regulation, 205
drawing, 234, 235, 241
drought, 165, 166, 174, 177, 178
drug carriers, 83
drug design, 233
drug discovery, 89, 116, 119, 146, 157, 233
drug metabolism, 157, 233, 240
drug therapy, 203
drug toxicity, 203
drug treatment, 210
drugs, 80, 81, 82, 96, 203, 206, 232, 240
duality, 73, 75
dynamical systems, 12, 102
E
E.coli, 231
ECM, 99, 101
ecology, x, 163, 170, 172, 176, 182, 183, 186, 194,
198, 199, 200
ecosystem, 164, 167, 170, 178, 182, 184, 186, 187,
188, 189, 190, 191, 194, 195, 199
editors, 114
effluent, 131
effluents, 148
egg, 205
eigenvalues, 12, 13, 14, 40, 41, 42, 43, 47, 48, 73,
74, 75, 76, 77
electric field, 137
electron, 131
electrophoresis, ix, 121, 128, 150, 156, 157, 194,
198, 205
ELISA, 210
elongation, 58
elucidation, 122, 233
embryonic stem cells, 111
emergent populations, vii, 1
emission, 88, 159, 166, 178, 194, 220
emitters, 138
encephalopathy, 145
encoding, 183, 185, 186, 188, 189, 191, 193, 195,
196
endocrine, 116
endothelial cells, 95, 117
engineering, xii, 116, 118, 130, 182, 187, 230, 239
entropy, 219
environmental conditions, 37, 91, 94
environmental factors, 37, 172, 173, 203, 208
environmental impact, x, 201
environmental influences, 205, 206
environmental stimuli, 205, 238
environmental sustainability, 194
enzyme induction, 233, 240
enzymes, xi, 38, 89, 90, 91, 92, 93, 94, 95, 96, 97,
98, 109, 175, 182, 183, 185, 187, 188, 189, 190,
191, 192, 193, 194, 195, 197, 199, 216, 218, 229,
231, 232, 233, 238, 239, 244, 247, 249
eosinophilia, 81
epidemiology, 202
epithelial cells, xii, 106, 243, 249, 251
equilibrium, 8, 12, 13, 14, 36, 166, 244
ESI, ix, 121, 122, 128, 133, 134, 138, 139, 140, 141,
142, 155
estrogen, xii, 243, 244, 245, 246, 247, 248, 249, 250,
251
ethanol, 130, 149, 188, 191
etiology, xii, 243
evolutionary computation, 145
excretion, 124
execution, 222
experimental condition, ix, 4, 108, 122, 139, 143,
167
experimental design, 129, 138, 206
expertise, 232
exploitation, x, 181
exploration, 81, 169
exposure, 96, 122, 167, 168, 174, 177, 203
extracellular matrix, 99, 101, 117, 119, 213
extraction, x, 41, 85, 91, 127, 129, 130, 132, 143,
152, 161, 181, 184, 191, 197, 206
F
family history, 171
fantasy, 112
fatty acids, 93, 105, 108, 190, 192, 204
feces, 193
fermentation, 190, 193, 194
fertility, 204, 212
fiber, 111, 115, 192, 193
fibroblasts, 95
field trials, 178
films, 141
fingerprints, 18, 91, 166, 168, 173, 206, 216
first dimension, 131
flame, 152
flavonoids, 154, 177, 179
flexibility, 15, 16, 37
flora, ix, 82, 163, 178, 183, 187, 189, 195, 198
fluctuations, 4, 5, 36, 38, 51
fluid, 145, 190, 194