Breast cancer: A comparison of response to endocrine therapy and oestrogen excretion patterns including unusual metabolites (original) (raw)
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Maturitas, 2009
Purpose Two main estradiol metabolites have different biological behavior with tumorigenic features of 16-OHE1 and antiproliferative characteristics of 2-OHE1. We investigated the ratio of these estradiol metabolites in preand postmenopausal patients with breast cancer (BC) within two case-control studies. Methods From 41 premenopausal patients with (cases) and without (controls N = 211) BC and 207 postmenopausal patients with and without BC (N = 206), urine samples were collected. Urine samples were collected prior to surgery and stored at-20°C until measurement by ELISA. The multiple linear regression test with two interactions was performed to evaluate the influence of different factors on the metabolic ratio. Results In premenopausal patients, log ratio of 2-OHE1/ 16-OHE1 was 0.25 (CI 0.20;0.29) and 0.21 (CI 0.11;0.31) for controls and cases without significant difference. In postmenopausal patients, log ratio was 0.22 (CI 0.17;0.26) and 0.11 (CI 0.07;0.15) in controls and cases, respectively, and was statistically significantly lower (p = 0.0002). Log ratio was significantly influenced by BMI, but only in postmenopausal patients, an increased BMI resulted in a significantly (p \ 0.042) decreased ratio. Conclusions Our case control studies suggest that in postmenopausal women a different metabolism of estrogens may play a role in the tumorigenesis of breast cancer. This genetically determined metabolism could be influenced by the exogenic factor BMI. In premenopausal women different hormone levels at different time points of the menstrual cycle may be an explanation that why we could not find an influence of estrogen metabolism.
Journal of steroid biochemistry, 1989
The effect of aminoglutethimide treatment on urine estrogen glucuronide excretion was investigated using injections of [4-14C]estradiol (4 women) or [4-14C]estrone (2 women). Each patient received 25 mu Ci of either [4-14C]estradiol or [4-14C]estrone as a bolus injection before initiation of aminoglutethimide treatment, and an equal injection following 3-20 weeks on treatment with aminoglutethimide 250 mg q.i.d. with hydrocortisone (50 mg b.i.d. for 2 weeks, then 25 mg b.i.d.). Urine was collected for 24-72 h following each injection. Aminoglutethimide treatment caused significant alterations in the metabolite profiles of estradiol and estrone but with large interindividual variations. [14C]Estriol glucuronide excretion was increased by a median value of 48.6%. [14C]16 alpha-Hydroxyestrone glucuronide and [14C]16-epi-estriol glucuronide excretion was increased by median values of 16.3 and 37.7% respectively, and [14C]2-hydroxyestriol glucuronide excretion was increased by a median v...
Plasma and urinary oestrogens in breast cancer patients on treatment with 4-hydroxyandrostenedione
British journal of cancer, 1993
Plasma and urinary oestrogens were measured in nine breast cancer patients (eight postmenopausal women and one man) before and during treatment with the aromatase inhibitor 4-hydroxyandrostenedione. Urinary oestrogens were measured by using a highly specific GC-MS method. Plasma levels of oestrone, oestradiol and oestrone sulphate were suppressed by 66.6% (+/- 3.6%), 57.7% (+/- 5.1%) and 51.8% (+/- 6.4%) respectively (P < 0.005 for all). Twenty-four hour urinary excretion of total oestrogens, oestradiol, oestriol, 2-hydroxyoestrone, 16 alpha-hydroxyoestrone and the minor metabolites 16 beta- and 15 alpha-hydroxyoestrone were all suppressed by mean values ranging from 60% to 82%, (oestradiol: P < 0.025, otherwise P < 0.005). There were no significant changes in the ratios between the different plasma oestrogens. The finding of sustained plasma and urinary oestrogens at 20-40% compared to their control levels indirectly support a hypothesis of alternative oestrogen sources in...
Studies of oestrogen metabolism in postmenopausal women with cancer
Journal of steroid biochemistry, 1981
Metabolic clearance rates (MCR) and production rates (PR) for oestrone (El) and oestradiol (E2) were measured in six menonausal subjects with endometrial cancer, five with endometrial hyperplasia and two normal women. Significant correlations were found between the percent ideal body weight (%IBW) and MCR-El (r = 0.84. P c 0.01) and YIBW and PR-El (r = 0.65. P < 0.09. The MCR-E2 were elevated in all subjects with endometrial'&cer (1488 + 203 i/24 h, mean f SDX but PR-ES was only significantly elevated (101.4 &24 h) in one subject with endometrial cancer. Plasma concentrations of El and E2 were measured in postmenopausal women with breast cancer, but no significant differences from normal were detected. The free fraction of oestradiol, however, was significantly greater (P < 0.02) in women with benign (1.9 f 3%) or malignant (1.9 f 0.4%) breast disease compared with normal women (1.6 * 0.4%). The in uirro conversion of androstenedione to El and El to E2 was measured in samples of adipose tissue. Higher rates of El (range, 1.24Ipg/mg protein/3 h) and E2 (range, 0.6-15.2 pg/mg protein/3 h) production were found in tissue from women aged 40-50 years compared with rates measured using tissue from younger women. Adipose tissue samples obtained from five women with endometrial cancer did not show a consistent increase in conversion of androstenedione to oestrone or El to E2 compared with normal women of similar age and weight.
Tissue content of hydroxyestrogens in relation to survival of breast cancer patients
Clinical Cancer Research
The main goal of our study was to assess estrogen contents of breast tumor tissues, having different estrogen receptor status, in relation to long-term follow-up of patients. Experimental Design: Twenty-one breast cancer cases, all collected from January 1986 to January 1988 at the M. Ascoli Cancer Hospital Centre in Palermo, were included in the study and compared with 6 healthy women as a control group. Average follow-up time of patients was 144 +/- 10 months. The estrogen receptor status of tissues was determined by both ligand binding and immunohistochemical assays. A high performance liquid chromatography-based approach, jointly with gas chromatography/mass spectrometry, was used to identify and measure main estrogens, various hydroxyestrogens, and their methoxy derivatives in both normal and tumor tissues. Although variable concentrations of hydroxylated estrogens were detected, they consistently accounted for >80% of all of the estrogens. Significantly greater amounts of b...
Urinary estrogen metabolites and breast cancer: a combined analysis of individual level data
The International Journal of Biological Markers, 2012
The products of estrogen metabolism may affect breast carcinogenesis. The 16␣-hydroxyestrone (16-OHE) metabolite has a higher affinity for the estrogen receptor (ER) than the 2-hydroxyestrone (2-OHE) metabolite, while conjugated 2-OHE metabolite may inhibit angiogenesis. We investigated the association between the relative concentrations of these metabolites in urine (2-OHE/16-OHE) and breast cancer in a case-control study of Chinese women living in Shanghai. Methods: Incident breast cancer cases between 25 and 65 years of age (n = 110) were identified from hospital or population tumor registries in Shanghai, China. Controls (n = 110) were randomly selected from a complete registry of the Shanghai population, and individually matched to cases by menopausal status, age, and pre-treatment or post-treatment urine collection time. Urine samples were collected prior to any breast cancer treatment or surgery among 78 case-control pairs, while urine was collected after surgery, and perhaps other treatments, among 32 case-control pairs. A commercial enzyme-immunoassay kit was used to measure urinary estrogen metabolite concentrations. Conditional logistic regression was used to calculate odds ratios summarizing the 2-OHE/16-OHE and breast cancer association within subjects providing either pre-treatment or post-treatment urine samples. Results: Subjects with a higher urinary 2-OHE/16-OHE ratio were less likely to be diagnosed with breast cancer, but only when urine samples were collected prior to breast cancer treatment (OR Tertile 3 (T3) versus Tertile 1 (T1) = 0.5, 95% CI (0.2, 1.1)). In contrast, a higher 2-OHE/16-OHE ratio was significantly associated with breast cancer among subjects providing urine specimens after treatment initiation (OR T3 versus T1 = 8.7, 95% CI (1.6, 47.1)). This observed cross-over modification occurred within both pre-menopausal and post-menopausal women, and independent of body mass index or recent dietary intake. Conclusion: Cross-study differences in urine collection protocols may explain observed inconsistencies in the 2-OHE/16-OHE and breast cancer association. Our case-control analysis using pre-treatment urine samples suggested that a lower 2-OHE/16-OHE ratio was associated with an increased risk of pre-menopausal and post-menopausal breast cancer diagnosis among Chinese women.
Steroids, 2003
The products of estrogen metabolism may affect breast carcinogenesis. The 16alpha-hydroxyestrone (16-OHE) metabolite has a higher affinity for the estrogen receptor (ER) than the 2-hydroxyestrone (2-OHE) metabolite, while conjugated 2-OHE metabolite may inhibit angiogenesis. We investigated the association between the relative concentrations of these metabolites in urine (2-OHE/16-OHE) and breast cancer in a case-control study of Chinese women living in Shanghai. Incident breast cancer cases between 25 and 65 years of age (n=110) were identified from hospital or population tumor registries in Shanghai, China. Controls (n=110) were randomly selected from a complete registry of the Shanghai population, and individually matched to cases by menopausal status, age, and pre-treatment or post-treatment urine collection time. Urine samples were collected prior to any breast cancer treatment or surgery among 78 case-control pairs, while urine was collected after surgery, and perhaps other treatments, among 32 case-control pairs. A commercial enzyme-immunoassay kit was used to measure urinary estrogen metabolite concentrations. Conditional logistic regression was used to calculate odds ratios summarizing the 2-OHE/16-OHE and breast cancer association within subjects providing either pre-treatment or post-treatment urine samples. Subjects with a higher urinary 2-OHE/16-OHE ratio were less likely to be diagnosed with breast cancer, but only when urine samples were collected prior to breast cancer treatment (OR(Tertile3(T3)versusTertile1(T1))=0.5, 95% CI (0.2, 1.1)). In contrast, a higher 2-OHE/16-OHE ratio was significantly associated with breast cancer among subjects providing urine specimens after treatment initiation (OR(T3versusT1)=8.7, 95% CI (1.6, 47.1)). This observed cross-over modification occurred within both pre-menopausal and post-menopausal women, and independent of body mass index or recent dietary intake. Cross-study differences in urine collection protocols may explain observed inconsistencies in the 2-OHE/16-OHE and breast cancer association. Our case-control analysis using pre-treatment urine samples suggested that a lower 2-OHE/16-OHE ratio was associated with an increased risk of pre-menopausal and post-menopausal breast cancer diagnosis among Chinese women.
Comparison of estrogens and estrogen metabolites in human breast tissue and urine
Reproductive Biology and Endocrinology, 2010
Background: An important aspect of the link between estrogen and breast cancer is whether urinary estrogen levels are representative of the intra-tissue levels of bioavailable estrogens. Methods: This study compares 15 estrogen and estrogen metabolite levels in breast tissue and urine of 9 women with primary breast cancer using a quantitative liquid chromatography-mass spectrometry method. Results: The average levels of estrogens (estrone, 17 beta-estradiol) were significantly higher in breast tissue than in urine. Both the 2 and the 16-hydroxylation pathways were less represented in breast tissue than urine; no components of the 4-hydroxypathway were detected in breast tissue, while 4-hydroxyestrone was measured in urine. However, the 2/16 ratio was similar in urine and breast tissue. Women carrying the variant CYP1B1 genotype (Leu/Val and Val/Val) showed significantly lower overall estrogen metabolite, estrogen, and 16-hydroxylation pathway levels in breast tissue in comparison to women carrying the wild type genotype. No effect of the CYP1B1 polymorphism was observed in urinary metabolites. Conclusions: The urinary 2/16 ratio seems a good approximation of the ratio observed in breast tissue. Metabolic genes may have an important role in the estrogen metabolism locally in tissues where the gene is expressed, a role that is not readily observable when urinary measurements are performed.
Analytica Chimica Acta, 2012
A rapid, sensitive, specific and accurate analytical method of ultra-fast liquid chromatography combined with tandem mass spectrometry (UFLC-MS/MS) was established for simultaneous quantitative analysis of 16 distinct endogenous estrogens and their metabolites (EMs) in postmenopausal female urine. The quantitative method utilized a hydrolysis/extraction/derivatization step and a UFLC system to achieve separation in 16 min. The lower limit of quantitation for each estrogen metabolite was 2 pg mL −1 with the percent recovery of a known added amount of estrogen at 93.2-109.3%. The intra-batch accuracy and precision for all analytes were 87.5-107.7% and 0.6-11.7%, respectively, while inter-batch accuracy and precision were 87.0-105.8% and 1.2-10.2%, respectively. Using this developed and validated method, the comprehensive metabolic profiling of 16 EMs in urine samples of 86 postmenopausal female breast cancer patients and 36 healthy controls was investigated by systematic statistical analysis. As a result, the circulating levels of 6 EMs were found to be different by a comparison of patients and healthy controls. The parent estrogens, estrone (E1) and 17-estradiol (E2), as well as 2-hydroxyestradiol (2-OHE2) and 4-hydroxyestradiol (4-OHE2) were produced in higher abundance, whereas 16␣-hydroxyestrone (16␣-OHE1) and 2-methoxyestradiol (2-MeOE2) were decreased in the breast cancer group. 2-OHE2 and 4-OHE2 in particular showed significant elevation in patients, which are consistent with the carcinogenic mechanism hypothesis that catechol estrogens can react with DNA via quinones, resulting in mutations to induce breast cancer. Thus, 2,4-hydroxylation may be the dominant metabolic pathway for parent estrogens rather than 16␣-hydroxylation. The lower level of 2-MeOE2 in the breast cancer group was believed to correlate with its protective effect against tumor formation. This study could provide valuable information on the association of the EM metabolic pathway with carcinogenesis as well as identify potential biomarkers for estrogen-induced breast cancer risk.