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Effects of Endogenous and Exogenous Hormones on the Female Breast: With Special Reference to the Expression of Proteoglycans
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis aims to study the effects of endogenous and exogenous hormones and mammographic breast density (BD) on cellular markers in non-cancerous female breast tissue. Women on the waiting list for breast reduction plastic surgery were recruited (n = 79), and randomized to 2 months of hormone therapy or no therapy before surgery. The women had a mammogram and a needle biopsy 2 months before surgery and tissue samples were obtained at the operation.

In premenopausal women, estrogen receptor (ER)α levels were associated with age (p = 0.0002), were similar in the follicular and luteal phases of the menstrual cycle and were higher in parous than in nulliparous women (p = 0.009). Current smokers had lower PR levels than non-smokers (p = 0.019). Women on oral contraception had lower ERα (p = 0.048) and PR (p = 0.007) levels than women in the follicular phase. The ERα levels did not differ significantly between postmenopausal estrogen and estrogen-progestogen users, but PR levels were lower among estrogen-progestogen users (p = 0.03).

We found lower expression of the genes for decorin and syndecans 1 and 4 in the luteal phase than in the follicular phase, among parous women. Protein levels of the androgen receptor, syndecan-4 and decorin was lower in premenopausal women who were using oral contraceptives (OC) than in those in the follicular phase (p = 0.002 - 0.02), whereas no significant differences between OC use and the luteal phase were found.

In premenopausal women, BD was negatively associated with age and body mass index but was similar for the menstrual phases. Breast density was associated with genetic expression of the androgen receptor and remained significant after adjustment for age (rs = 0.56; p = 0.04). After adjustement for age, breast density was also marginally associated with expression of the caspase 3 gene (0.55; 0.053). However, protein levels of caspase 3 was negatively associated (-0.61; 0.03).

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2011. , 76 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 651
Keyword [en]
breast tissue, proteoglycans, mammographic density, oral contraceptives, androgen receptor, proliferation, apoptosis, extracellular matrix, premenopausal
National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
Obstetrics and Gynaecology
Identifiers
URN: urn:nbn:se:uu:diva-147793ISBN: 978-91-554-8018-9OAI: oai:DiVA.org:uu-147793DiVA: diva2:400873
Public defence
2011-04-14, Auditorium Minus, Museum Gustavianum, Akademigatan 3, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2011-03-23 Created: 2011-02-28 Last updated: 2011-05-04Bibliographically approved
List of papers
1. Effects of pre-and postmenopausal use of exogenous hormones on receptor content in normal human breast tissue: A randomized study
Open this publication in new window or tab >>Effects of pre-and postmenopausal use of exogenous hormones on receptor content in normal human breast tissue: A randomized study
2008 (English)In: Gynecological Endocrinology, ISSN 0951-3590, Vol. 24, no 8, 475-480 p.Article in journal (Refereed) Published
Abstract [en]

Objective. To examine the effects of exposure to endogenous and exogenous hormones on estrogen receptor- (ER) and progesterone receptor (PR) levels in normal human breast tissue. Methods. In a randomized study of women scheduled for mammary reduction plasty (n = 81), ER and PR content in breast parenchyma was analyzed in premenopausal (n = 49) and postmenopausal (n = 16) women. Premenopausal women were randomized to surgery in the follicular or luteal phase of the menstrual cycle or after oral contraceptive treatment for 2 months. Postmenopausal women were randomized to sequential or estrogen-only therapy for 2 months prior to surgery. Results. ER content was higher in parous than in nulliparous (p = 0.009) premenopausal women and displayed a positive association with age (rs = 0.51, p = 0.0002). Compared with premenopausal women in the follicular phase, postmenopausal women had higher ER content (p = 0.040) whereas premenopausal women on oral contraception had lower ER (p = 0.048) and PR (p = 0.007) content. Smokers had lower PR content than non-smokers (p = 0.02). Conclusion. In the present study ER content was higher in parous than in non-parous women and associated with premenopausal age. Short-term oral contraceptives yielded lower ER and PR contents. Postmenopausal estrogen/progestogen combined therapy yielded lower PR content than estrogen-only therapy.

Keyword
Estrogen receptor-a, human breast tissue, oral contraceptives, postmenopausal, progesterone receptor, premenopausal
Research subject
Identifiers
urn:nbn:se:uu:diva-86532 (URN)10.1080/09513590802234204 (DOI)000260457200010 ()
Available from: 2008-12-03 Created: 2008-11-12 Last updated: 2011-05-04Bibliographically approved
2. The expression of syndecan-1, syndecan-4 and decorin in healthy human breast tissue during the menstrual cycle
Open this publication in new window or tab >>The expression of syndecan-1, syndecan-4 and decorin in healthy human breast tissue during the menstrual cycle
2010 (English)In: Reproductive Biology and Endocrinology, ISSN 1477-7827, Vol. 8, 35-41 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: In order to unravel the interactions between the epithelium and the extra cellular matrix (ECM) in breast tissue progressing to cancer, it is necessary to understand the relevant interactions in healthy tissue under normal physiologic settings. Proteoglycans in the ECM play an important role in the signaling between the different tissue compartments. The proteoglycan decorin is abundant in the breast stroma. Decreased expression in breast cancer tissue is a sign of a poor tumor prognosis. The heparane sulphate proteoglycans syndecan-1 and syndecan-4 promote the integration of cellular adhesion and proliferation. The aim of this study was to investigate the gene expression and location of decorin, syndecan-1 and syndecan-4 in the healthy breast during the menstrual cycle. METHODS: Tissue from healthy women undergoing breast reduction plastic surgery was examined using immunohistochemistry (n = 38) and Real-Time RT-PCR (n = 20). Both parous and nulliparous women were eligible and the mean age of the women was 34(+/- 10 years) with regular menstrual cycles (28 +/- 7 days). None of the women had used hormonal treatment the last three months. The women were randomized to needle biopsy two months before the operation in the follicular or luteal menstrual phase and for another biopsy at the operation in the opposite phase. Serum samples were obtained to characterize the menstrual phase. The Wilcoxon signed rank test and Mann Whitney test were used for statistical analyses. RESULTS: By real time-RT-PCR the gene signal for all three proteoglycans; decorin (p = 0.02) and syndecan-1 (p = 0.03) and syndecan-4 (p = 0.02) was significantly lower among parous women in the luteal phase than in the follicular phase. Immunohistochemistry confirmed the identification of the proteins but no significant difference between menstrual phases was observed. Serum samples verified the menstrual phase. CONCLUSIONS: Our study shows, for the first time in the healthy breast, a significantly lower expression of the genes for the three proteoglycans, decorin, syndecan-1 and syndecan-4 in the luteal phase during the menstrual cycle. These changes were registered under normal physiologic conditions. Since ECM molecules appear to be involved in tumor progression, these findings in the normal breast could constitute a base for further studies in women receiving hormonal therapy or those with breast cancer.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-135941 (URN)10.1186/1477-7827-8-35 (DOI)000277406700001 ()20398359 (PubMedID)
Available from: 2010-12-09 Created: 2010-12-09 Last updated: 2011-05-04Bibliographically approved
3. The effect of short-term oral contraceptive use on the expression of syndecan-1, syndecan-4, decorin and the androgen receptor in breast tissue from women of fertile age
Open this publication in new window or tab >>The effect of short-term oral contraceptive use on the expression of syndecan-1, syndecan-4, decorin and the androgen receptor in breast tissue from women of fertile age
2011 (English)In: The Breast Journal, ISSN 1075-122X, E-ISSN 1524-4741Article in journal (Other academic) Submitted
Abstract [en]

Background

In non-cancerous breast tissue from premenopausal women, we examined gene expression and protein levels of the androgen receptor and the proteoglycans decorin, syndecan-1 and syndecan-4, before and after use of oral contraceptives (OC).

Material and Methods

Premenopausal women (n = 20) undergoing breast reduction plastic surgery, received two months use of  combined oral contraceptive with ethinylestradiol 30μg and levonorgestrel 150μg. Breast tissue was sampled at mammography (needle biopsy) two months before and at the operation. We analysed immunohistochemistry (n = 20) and real-time RT-PCR (n = 10).

Results

After two months of OC use, we found a significant decrease in the protein levels of syndecan-4 (p = 0.003), the androgen receptor (p = 0.002) and decorin (p = 0.018), but not of syndecan-1 protein, compared to expression during the follicular phase in the normal menstrual cycle before OC use.  Real- time RT-PCR indicated a significant decrease in gene expression for decorin (p = 0.002).  

Conclusions

In pre-menopausal women, short-term OC use yielded lower protein levels of syndecan-4, the androgen receptor and decorin, and lower gene expression for decorin, compared to that during the follicular phase of the menstrual cycle before OC use.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-147741 (URN)
Available from: 2011-02-28 Created: 2011-02-28 Last updated: 2011-10-27Bibliographically approved
4. Mammographic breast density and the expression of androgen receptor, caspase 3, Ki67 and proteoglycans in pre-menopausal women.
Open this publication in new window or tab >>Mammographic breast density and the expression of androgen receptor, caspase 3, Ki67 and proteoglycans in pre-menopausal women.
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Abstract

 

Background: Mammographic breast density (BD) is a strong risk factor for breast cancer, but underlying histopathological correlates are not fully understood. In the human breast the main part of the volume constitutes of stroma. We examined the correlation between BD and Ki67, caspase 3, androgen receptor (AR), syndecan-1 , syndecan –4 and decorin in pre-menopausal non cancerous breast tissue.

Method: Pre-menopausal women (n = 55), planned for a reduction mammoplasty and having a breast sample (needle biopsy) at the same time of preoperative mammography, were included. Protein levels of the proteoglycans syndecan-1, syndecan-4, decorin and the AR, Ki67 and caspase 3, were examined by immunohistochemistry (IHC) and gene expression by real-time RT-PCR. Results were compared with regard to BD class (< 20% vs. > 40%) and mean BD (%), using non-parametric analysis and adjustments. 

Results: BD (%) decreased significantly with age (p < 0.0001) and with BMI (p = 0.002) but was similar in the follicular and luteal phases. The AR gene expression increased significantly with increasing BD class and with mean BD% (rs = 0.43; p = 0.048, for both), and was strengthened after adjustment for age. After adjustment for age, caspace 3 was positively associated with mean BD (%), with borderline significance (0.55; 0.053), whereas IHC was negatively associated to BD class (-0.61; 0.026). PCR values for Ki67, syndecan-1 and syndecan-4 were numerically higher in dense breasts (p > 0.05 for all).

Conclusion: In pre-menopausal women, gene expression for AR and caspase 3 increased, whereas protein levels of caspase 3 might decrease, with increasing breast density. This limited study showed no significant associations between Ki67, syndecans, decorin and breast density.

 

Keyword
mammographic breast density, proteoglycans, premenopausal
Research subject
Obstetrics and Gynaecology
Identifiers
urn:nbn:se:uu:diva-147784 (URN)
Available from: 2011-02-28 Created: 2011-02-28 Last updated: 2011-05-04

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