© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 21, 1893,
November 3, 1999
© 1999 Oxford University Press
CORRESPONDENCE |
Re: Urinary 2-Hydroxyestrone/16
-Hydroxyestrone Ratio and Risk of Breast Cancer in Postmenopausal Women
Affiliations of authors: L. A. M. Castagnetta, Institute of Oncology, University Medical School and Experimental Oncology, Palermo Branch of Istituto Scientifico Tumori-Genoa, c/o M. Ascoli Cancer Hospital Center, Palermo, Italy; G. Carruba, Institute of Oncology, University Medical School.
Correspondence to: Luigi A. M. Castagnetta, Ph.D., Istituto di Oncologia, Via Marchese Ugo 56, 90141 Palermo, Italy (e-mail: lucashbl{at}unipa.it).
We have read with interest the paper by Ursin and colleagues
(1) on the ratio of urinary 2-hydroxyestrone
(2-OHE1) to 16
-hydroxyestrone (16-OHE1)
and the risk of breast cancer in postmenopausal women. Interpretation was,
however, hindered by some issues related to both case subjects and methods.
Enrollment of surviving women from a previous population-based, case-control study (2), as well as exclusion of those with previous use of chemotherapeutic
agents, likely included patients with a more favorable prognosis—that is, those subjects
who could have had a higher 2-OHE1/16-OHE1 ratio according to
the "good estrogen" theory (3). In addition, although the
report by Ursin et al. apparently contradicts previous evidence supporting the hypothesis of
"good estrogen," comparisons of the data should be made cautiously. The
respective methods used for assessment of estrogen metabolism differ substantially (e.g.,
tritium-release radiometric method in the report by Schneider et al. (4)
and enzymeimmunoassay or radioimmunoassay in the present study), as do the criteria used for
selection of both case subjects and control subjects.
More important, two major concerns emerged. First, patients in the study were diagnosed for
breast cancer from March 1987 through December 1989 or from January through December
1992, while urine collection was conducted from 1993 through 1996, with a lag period of 3-7
years. This point represents a critical issue, since assessment of breast cancer risk in relation to
excretion levels of either 2-OHE1, 16-OHE1, or their ratios would
ideally be based on preclinical measurements of urinary hydroxyestrogens in a prospective study
of healthy women, where incident breast cancer case subjects are compared with matched control
subjects who do not develop mammary tumors. Furthermore, any breast tumor-associated change
in the patterns of urinary estrogens may vanish given such a long period (from 3 to 7 years) after
surgery, thus invalidating inferences.
Second, excretion levels of both 2-OHE1 and 16-OHE1 can
hardly be considered entirely representative of hydroxylated estrogens, since they do not take into
account the amounts of methoxy (MeO) derivatives, specifically 2-MeOE1, that can
be readily produced by both tissue and erythrocyte catechol-O-methyltransferase (COMT)
enzyme and excreted in abundant amounts in urine (5). On the other hand,
urinary 16-OHE1 may not reflect the actual production rates of this metabolite,
since it has been reported to covalently bind amino groups on nucleotides in target cell nuclei (6) so that its tissue content may be several-fold greater than respective
plasma or urine levels. Therefore, intratissue concentrations of 16-OHE1 would
represent a more appropriate indicator of its formation. Preliminary data from current studies in
our laboratories seem to indicate that intratissue content of 2-OHE1 is statistically
significantly greater (P<.02) in breast cancer patients who have longer survival after
relapse (Castagnetta L, Granata OM, Traina A, Carruba G: unpublished data).
In conclusion, while the study by Ursin and colleagues does not resolve the existing controversies on the potential role of hydroxylated estrogens in breast cancer development, it may lead the reader to assume that modulation of estrogen hydroxylating enzymes could not serve as a basis for the development of chemopreventive measures. This conclusion conflicts with the effectiveness of this kind of chemoprevention suggested experimentally (7).
REFERENCES
1
Ursin G, London S, Stanczyk FZ, Gentzschein E, Paganini-Hill
A, Ross RK, et al. Urinary 2-hydroxyestrone/16-hydroxyestrone ratio and risk of breast
cancer in postmenopausal women. J Natl Cancer Inst 1999;91:1067-72.
2 Longnecker MP, Paganini-Hill A, Ross RK. Lifetime alcohol consumption and breast cancer risk among postmenopausal women in Los Angeles. Cancer Epidemiol Biomarkers Prev 1995;4:721-5.[Abstract]cancerlit;96114047
3 Bradlow HL, Telang NT, Sepkovic DW, Osborne MP. 2-Hydroxyestrone: the `good' estrogen. J Endocrinol 1996;150 Suppl:S259-65.[Abstract]cancerlit;97099229
4
Schneider J, Kinne D, Fracchia A, Pierce V, Anderson KE,
Bradlow HL, et al. Abnormal oxidative metabolism of estradiol in women with breast cancer. Proc Natl Acad Sci U S A 1982;79:3047-51.
5 Merriam GR, Brandon DD, Kono S, Davis SE, Loriaux DL, Lipsett MB. Rapid metabolic clearance of the catechol estrogen 2-hydroxyestrone. J Clin Endocrinol Metab 1980;51:1211-3.[Abstract]
6
Yu SC, Fishman J. Interaction of histones with estrogens.
Covalent adduct formation with 16-hydroxyestrone. Biochemistry 1985;24:8017-21.[CrossRef][Medline]
7 Bradlow HL, Sepkovic DW, Telang NT, Osborne MP. Indole-3-carbinole. A novel approach to breast cancer prevention. Ann N Y Acad Sci 1995;768:180-200.[Abstract]cancerlit;96098078
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