Estradiol Increases IL-8 Secretion of Normal Human Breast Tissue and Breast Cancer In Vivo

Abstract

IL-8 or CXCL8 has been associated with tumor angiogenesis, metastasis, and poor prognosis in breast cancer. Estrogen is crucial in breast carcinogenesis and tumor progression. Whether sex steroids affect IL-8 secretion of normal breast tissue or breast cancer is not known. Several cell types in a tissue secrete IL-8. Hence, regulatory mechanisms of IL-8 need to be investigated in whole tissue. We used microdialysis to sample IL-8 in normal human breast tissue in situ in pre- and postmenopausal women, preoperatively in breast cancers of women, and in experimental breast cancer in mice. We found a significant positive correlation between IL-8 and estradiol in normal breast tissue and hormone-dependent breast cancer in vivo. Ex vivo, estradiol exposure increased the IL-8 secretion of normal whole breast tissue in culture. In experimental breast cancer, estradiol increased IL-8 whereas the anti-estrogen tamoxifen inhibited the secretion of IL-8 both in vitro and extracellularly in vivo in tumors of nude mice. An anti-IL-8 Ab inhibited endothelial cell proliferation induced by cancer cell produced IL-8 and tumors with low IL-8 levels exhibited decreased angiogenesis. Our results strongly suggest that estradiol has a critical role in the regulation of IL-8 in normal human breast tissue and human breast cancer. IL-8 may present a novel therapeutic target for estrogen driven breast carcinogenesis and tumor progression.

Dense breast tissue in postmenopausal women is associated with a pro-inflammatory microenvironment in vivo

“…Sampling of extracellular molecules is possible by using microdialysis and this technique has been used to sample bioactive molecules present in situ in both normal and malignant human breast tissues. 4,5,7,11,34 In the present study, we used microdialysis for sampling of cytokines and our data strongly suggest an inflammatory microenvironment in dense breast tissue. This was supported, not only by the significantly increased levels of individual cytokines in dense breast tissue, which may be released by all cell types in the microenvironment, but also by significant correlations between these inflammatory proteins in the breast.…”

“…We have previously found an association of estrogen levels and the in vivo levels of several inflammatory biomarkers in human breast tissue. 4,5,7,9,11,34 In these studies, both pre-and post-menopausal women and patients investigated before and after anti-estrogen treatment were included, thus reflecting cohorts of women with a wide range of hormone levels, whereas in the present study, postmenopausal women exhibiting minor variation of estradiol levels were included. Hence, correlations with estrogen may not be expected in this selected population.…”

“…One microdialysis catheter was placed in the upper lateral quadrant of the left breast and directed toward the nipple as previously described 5,7,8,34,[43][44][45][46][47][48] and one reference catheter was placed in abdominal subcutaneous fat. Microdialysis catheters (71/M Dialysis AB, Stockholm, Sweden), which consists of a tubular dialysis membrane (length 20 mm, diameter 0.52 mm, and 100,000 atomic mass cut-off) glued to the end of a double-lumen tube (80 mm long £ 0.8 mm in diameter), were inserted via a splitable introducer (M Dialysis AB), connected to a microinfusion pump (M Dialysis AB) and perfused with NaCl 154 mmol/L and hydroxyethyl starch 60 g/L (Voluven Ò , Fresenius Kabi, Uppsala, Sweden), at a perfusion rate of 0.5 mL/min.…”

“…We have previously shown increased extracellular in vivo levels of several inflammatory mediators, such as interleukin (IL)-1, IL-8, chemokine (C-C motif) ligand (CCL) 2, CCL5, leptin, and vascular endothelial growth factor (VEGF) in breast cancers of women and an association with sex steroids of these factors in normal human breast tissue. [4][5][6][7][8][9][10][11][12] Mammographic density has been associated with increased risk of breast cancer. 13 In a meta-analysis women with >75% dense breast area have a 4-fold increased risk of developing breast cancer compared to women with <5% dense breast area.…”

Microdialysis Combined with Proteomics for Protein Identification in Breast Tumor Microenvironment In Vivo

“…Similarly, lysosomal protease Cathepsin D expression levels in the breast tumor environment were measured, and expression was shown to be inhibited by introduction of tamoxifen [12]. Recently, IL-8 was successfully collected from human breast tissues, using microdialysis, and findings suggested that estradiol increases IL-8 secretion in vivo [13].…”