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Variability of Vascular Endothelial Growth Factor in Normal Human Breast Tissue in Vivo during the Menstrual Cycle

Division of Gynecologic Oncology, University Hospital, Faculty of Health Sciences, SE-581 85 Linköping, Sweden

Address all correspondence and requests for reprints to: Charlotta Dabrosin, M.D., Ph.D., Division of Gynecologic Oncology, University Hospital, S-581 85 Linköping, Sweden. E-mail: lotda{at}imk.liu.se.

	Abstract

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Exposure to sex steroids increases the risk of breast cancer, but the mechanisms are poorly understood. Angiogenesis is crucial in tumor development and progression. Very little is known about the regulation of angiogenesis in the normal breast. Vascular endothelial growth factor (VEGF) has a key stimulatory role in angiogenesis. Interferon-inducible protein 10 (IP-10) is a potent inhibitor of angiogenesis in vivo. These factors function in autocrine/paracrine pathways; therefore, direct measurements in the target tissue are needed. I measured VEGF and IP-10 in normal human breast tissue in situ in healthy women, using microdialysis, in the follicular and luteal phase of the menstrual cycle. In breast tissue, VEGF levels increased in the luteal phase, compared with the follicular phase (17.8 ± 4 pg/ml to 34 ± 9 pg/ml, P < 0.05). Plasma VEGF did not show a cyclic variation (10.6 ± 2.8 pg/ml vs. 14.6 ± 3.5 pg/liter, P = 0.3). IP-10 levels did not vary during the menstrual cycle either in breast tissue (65 ± 17 pg/ml vs. 75 ± 21 pg/ml, P = 0.6) or in plasma (64 ± 7 pg/ml vs. 81 ± 10 pg/ml, P = 0.06). The data suggests that, in the luteal phase, VEGF and IP-10, in the normal human breast, exhibit a proangiogenic profile. This may be one mechanism by which sex steroids contribute to breast cancer development.

	Introduction

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THE BREAST IS a target organ for sex steroids, and long-term exposure to these hormones increase the risk of breast cancer (1, 2, 3). However, the pathophysiological mechanisms behind this increase are still not fully understood. During the process of transformation to malignancy, proliferation rate, as well as the levels of growth factors, is important; and several studies have shown that these different factors are influenced by ovarian steroids in the breast (4, 5, 6, 7). Angiogenesis is another key factor in tumor development, tumor progression, and metastasis, but little is known about its regulation in the breast (8).

Vascular endothelial growth factor (VEGF) is a potent stimulatory factor in angiogenesis (9, 10, 11). In breast cancer, VEGF mRNA expression is increased, compared with adjacent normal breast tissue (12). High VEGF levels correlate with poor prognosis and decreased overall survival for both node-positive and node-negative breast cancer patients (13, 14). Moreover, levels of VEGF protein measured by immunohistochemistry or immunoassay of tissue extracts correlate with microvessel density in invasive ductal carcinoma of the breast (15, 16).

Estrogen has been shown to modulate angiogenesis, both under physiological and pathological conditions, mainly via effects on endothelial cells (17). In the female reproductive tract, where angiogenesis is a normal physiologic event, as well as in endometrial and breast cancer, VEGF expression is regulated by sex steroids. Moreover, an estrogen-responsive element in the gene for VEGF has been identified (18, 19).

Several endogenous angiostatic factors play an important role in the regulation of angiogenesis, among which, interferon-inducible protein 10 (IP-10) has been suggested to be a strong inhibitor of angiogenesis in vivo (20, 21, 22, 23, 24). Whether sex steroids regulate IP-10 is not known.

VEGFs are bioactive as freely diffusible proteins in the extracellular space, where they become available to the endothelial cells (9). Because VEGF and IP-10 function via autocrine/paracrine action, a direct measurement of these cytokines in the specific organ is necessary. We have previously shown that microdialysis is a technique that enables direct measurements of molecules in the extracellular space in situ in human breast tissue (25, 26). In this study, microdialysis was used to determine VEGF and IP-10 in normal human breast tissue in vivo during the menstrual cycle in healthy women.

	Subjects and Methods

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Subjects

Eight healthy premenopausal women, 22–34 yr old, participated in the study. All women were free of medication and had a history of regular menstrual cycles (cycle length, 27–34 d). They had been off oral contraceptives for more than 3 months. The breasts were normal on clinical examination. The local ethical committee approved the study, and all women gave informed consent.

Experimental design

Microdialysis was performed twice during one menstrual cycle, in early follicular phase (d 1–3) and in the mid-luteal phase (d 21–26). Blood samples were collected from the women at each occasion to determine estradiol, progesterone, LH, FSH, and prolactin (PRL) to confirm the menstrual phases (estradiol and progesterone ELISA kits, DRG Instruments GmbH, Marburg, Germany; and AutoDELFIA, Wallac, Oy, Åbo, Finland).

The major part of the mammary gland in located in the upper lateral quadrant of the breast, and the left breast is affected with cancer slightly more often than the right breast; therefore, and because of ergonometric reasons, the microdialysis catheters were placed in this part of the left breast in all experiments. Before the insertion, 0.3 ml mepivacaine (5 mg/ml) was administrated intracutaneously. The catheters were inserted in the upper lateral quadrant of the breast and directed toward the nipple, as previously described (25, 26). With this procedure, I have shown that microdialysis is a reproducible technique for measurements in normal human breast tissue (25). There were no subsequent complications after the microdialysis experiments.

Microdialysis device

A microdialysis catheter (CMA 65; CMA Microdialysis AB, Stockholm, Sweden), which consists of a tubular dialysis membrane (30-mm long x 0.52-mm in diameter, 100,000 molecular weight cut-off) glued to the end of a double-lumen tube (80-mm long x 0.8-mm in diameter), was used. The catheters were inserted, guided by a catheter for iv use (Venflon, 1.4 mm; BOC Ohmeda AB, Helsingborg, Sweden). The catheters were connected to a microinfusion pump (CMA 107, CMA Microdialysis AB) and perfused with NaCl (154 mM) and dextran-70 (40 g/liter), at a perfusion rate of 0.5 µl/min. The solution entered the catheter through the outer tube and left it through the inner tube, from which it was collected. After a 30-min equilibration period, the outgoing perfusate was collected and stored at –70 C for subsequent analysis.

VEGF and IP-10 determination

Plasma was collected, on each occasion, using a glass tube containing sodium citrate (3.8%) as an anticoagulant, and was spun down and frozen at –70 C within 20 min of collection.

Microdialysate and plasma samples were analyzed for VEGF using a commercial quantitative immunoassay kit for human VEGF (QuantGlo, human VEGF; R&D Systems, Abingdon, UK). According to the manufacturer, this kit measures the VEGF 165 and 121 isoforms, and the sensitivity is less than 1.76 pg/ml, and intra-assay and interassay precision is 3–8%.

IP-10 was also analyzed using an ELISA kit (Quantikine, human IP-10; R&D systems). According to the manufacturer, this kit has a sensitivity of 1.67 pg/ml, and intra-assay and interassay precision is 3–8%. The precision of the ELISA kits was confirmed during the experiments. All samples were assayed in duplicate.

Statistics

Data are expressed as mean ± SEM. Student’s t test for paired observations was used. A P < 0.05 was considered as statistically significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Regular menstrual cycles

All women had regular menstrual cycles at the time of the investigation. Plasma levels of estradiol increased from 136 ± 8 pM in the follicular phase to 327 ± 40 pM in the luteal phase, P < 0.01. Progesterone levels increased from 1.2 ± 0.1 nM to 32 ± 3.3 nM, P < 0.0001.

Serum levels of PRL, FSH, and LH were within the normal range in all women. The characteristics of each individual volunteer are presented in Table 1.

In the breast, the extracellular levels of VEGF increased significantly in the luteal phase of the menstrual cycle, compared with the follicular phase (17.8 ± 4 pg/ml to 34 ± 9 pg/ml, P < 0.05, Fig. 1A). Plasma levels of VEGF did not show any significant change during the menstrual cycle (10.6 ± 2.8 pg/ml vs. 14.6 ± 3.5 pg/ml, P = 0.3, Fig. 1B). There was a wide range of the VEGF levels between individuals, which is important information when data from different women are compared. There were no correlations between serum estradiol levels and extracellular or plasma VEGF. Neither were there any correlations between serum progesterone levels and extracellular or plasma VEGF.

View larger version (16K): [in this window] [in a new window]   Figure 1. VEGF during the menstrual cycle. A, Extracellular levels of VEGF in normal human breast tissue, measured with microdialysis, in the follicular phase (d 1–3) and luteal phase (d 21–26) of the menstrual cycle, in eight women. VEGF increased significantly in the luteal phase, from 17.8 ± 4 pg/ml to 34 ± 9 pg/ml, P < 0.05. B, Plasma levels of VEGF during the menstrual phases, as described in A. There was no significant difference in the levels during the cycle.

There were no significant changes in extracellular levels of IP-10 in the breast during the menstrual cycle (65 ± 17 pg/ml in the follicular phase and 75 ± 21 pg/ml in the luteal phase), Fig. 2A. In plasma, the levels were similar to those measured in the extracellular space (64 ± 7 pg/ml in the follicular phase and 81 ± 10 pg/ml in the luteal phase), Fig. 2B.

View larger version (16K): [in this window] [in a new window]   Figure 2. IP-10 during the menstrual cycle. A, Extracellular levels of IP-10 in normal human breast tissue, measured with microdialysis, in the follicular phase (d 1–3) and luteal phase (d 21–26) of the menstrual cycle, in eight women. There was no significant difference during the cycle. B, Plasma levels of IP-10 during the menstrual phases, as in A. There was no significant difference during the cycle.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

Estrogens have been shown to regulate angiogenesis and increase VEGF expression in experimental breast cancer (18, 19), but very little is known about the regulation of angiogenesis in normal human breast. In the endometrium, both estrogen and progesterone regulate angiogenesis, and it has also been shown that progestins increase VEGF expression in human breast cancer cell lines (19, 27). The present data are in line with a previous study in baboons showing that VEGF mRNA levels increased in the mammary gland in the luteal phase of the cycle (28). These results suggest that sex steroids affect VEGF production in normal breast tissue, but it is uncertain whether this is an effect of estradiol only or whether progesterone also contributes to the regulation of VEGF.

Several isoforms of human VEGF containing 121, 165, 189, and 206 amino acids are produced from a single gene as a result of alternative splicing (29). The various isoforms differ in the affinity for heparin and heparin-like molecules, which affect their bioavailability (30). VEGF 121 is a secreted, freely soluble protein; VEGF 165 is also secreted, although a significant portion remains bound to the cell surface, whereas the larger isoforms bind tightly to heparin and are sequestered in the extracellular matrix (9). VEGFs are bioactive, as freely diffusible proteins in the extracellular space, where they become available to the endothelial cells; and it has been suggested that the free 121 isoform has greater angiogenic and tumorigenic properties than the heparin-bound isoforms (31). Previous assessments of VEGF protein have been performed by immunohistochemistry or immunoassay of tissue extracts (15, 16). These methods are tedious; and therefore, VEGF measured in blood has been considered as an alternative. The interpretation of such studies has, however, been complicated by the fact that serum VEGF, to a large part, is released from platelets, which are activated on coagulation (32). Unlike VEGF measured in serum, VEGF measured in plasma has been shown to be significantly higher in breast cancer patients, compared with control patients, but the plasma levels did not correlate with intratumoral VEGF assessed by immunohistochemistry (33). Moreover, the soluble bioactive forms of VEGF in the extracellular space cannot be detected by immunostaining of tissue sections (31, 34). Clearly, a direct measurement of VEGF locally in the target organ is therefore more accurate for determination of bioactive protein released in situ in the tissue of interest. This was also confirmed in the present study, where the increase of VEGF levels in the extracellular space in the target organ, the breast, was not detected in plasma.

VEGF is also known as vascular permeability factor, based on its ability to induce vascular leakage (9). Premenstrual breast tenderness and edema are common symptoms in women. At least 70% of healthy women report cyclical mastalgia in the luteal phase, but the mechanisms are not known (35, 36, 37). In the present study, all volunteers experienced various degrees of premenstrual tenderness during the experiment. The results, in this study, suggest that VEGF may be involved in the mechanisms that cause premenstrual mastalgia; and this opens for consideration of new treatment strategies for this common symptom.

It is not known whether the regulation of IP-10 could be influenced by sex steroids. Estradiol has been shown to increase IFN- production, and an estrogen-responsive element in the IFN- promoter has been found (38, 39). Because IP-10 is up-regulated by IFN-, there is a possibility also that IP-10 production may be affected by sex steroids (20). However, this remains to be elucidated, and the data in the present study did not demonstrate any change of IP-10 levels in vivo during the menstrual cycle, when the levels of estradiol and progesterone varied. Very little is known about sex steroid effects on other stimulatory and inhibitory factors important in angiogenesis. A few studies have found a relationship between estradiol and progesterone and mRNA levels of angiopoietin 1 and 2 in heart, kidney, and lungs tissue and fibroblast growth factor mRNA in endometrial tissue, but it is not known whether these factors are regulated in the same manner in breast tissue (40, 41).

Previous studies have shown that the proliferation rate of the breast epithelium peaks in the luteal phase of the menstrual cycle (4, 42). In the present study, the measured levels of VEGF and IP-10 exhibit a profile that may enhance angiogenesis in the breast in the luteal phase. Taken together, these findings suggest that estradiol, in combination with progesterone, not only stimulates the proliferation rate but also may promote angiogenesis in the normal breast. This may have implications for the increased incidence of breast cancer after exposure to sex steroids, and further investigation of the regulation of angiogenesis in the normal breast is needed.

	Footnotes

 
This work was supported by grants from The Swedish Cancer Foundation, Swedish Society of Medicine, Cancer Foundation of Östergötland, and research funds of Linköping University Hospital, Åke Wiberg, Percy Falk, and IVAX research foundations.

Abbreviations: IP-10, Interferon-inducible protein 10; PRL, prolactin; VEGF, vascular endothelial growth factor.

Received October 10, 2002.

Accepted February 28, 2003.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dabrosin, C. Search for Related Content PubMed PubMed Citation Articles by Dabrosin, C.