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Estradiol Increases IL-8 Secretion of Normal Human Breast Tissue and Breast Cancer In Vivo¹

Linköping University, Faculty of Health Sciences, Division of Oncology, University Hospital, Linköping, Sweden

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by grants from Swedish Cancer Society (Contract numbers 060036, 070012, and 070049), Swedish Research Counsil (Contract number 60294601), and Research Funds of Linköping University Hospital.

² Address correspondence and reprint requests to Dr. Charlotta Dabrosin, Professor of Oncology, Division of Oncology, University Hospital, S-581 85 Linköping, Sweden. E-mail address: charlotta.dabrosin{at}liu.se

³ Abbreviations used in this paper: ER, estrogen receptor; PgR, progesterone receptor; VEGF, vascular endothelial growth factor.