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Estrogenic Regulation of Host Immunity against an Estrogen Receptor–Negative Human Breast Cancer

Authors' Affiliations: ¹ Department of Pediatrics, ² Sealy Center for Vaccine Development, ³ Sealy Center for Environmental Health and Medicine, and ⁴ Department of Neuroscience and Cell Biology, University of Texas Medical Branch at Galveston, Galveston, Texas and Departments of ⁵ Biochemistry and ⁶ Child Health, University of Missouri-Columbia, Columbia, Missouri

Requests for reprints: Edward M. Curran, Department of Pediatrics, Sealy Center for Vaccine Development, 2.330G Children's Hospital, Galveston, TX 77555-0372. Phone: 409-772-0435; Fax: 409-772-0460; E-mail: emcurran{at}utmb.edu.

Purpose: The risk of developing breast cancer is positively correlated with exposure to increased levels of estrogen and/or an increased duration of estrogen exposure. Many different mechanisms have been proposed to explain the association of estrogens with breast cancer risk; however, the well-documented immune modulatory properties of estrogen have received little attention. In part, this is due to a lack of suitable models for studying this relationship.

Experimental Design: We have developed an animal model using estrogen receptor (ER)-negative human breast cancer cell line, MDA-MB-468, xenografted into severe combined immunodeficient (SCID) mice. We also generated the ER- knockout (ER-KO) mice on the SCID background and then tested the ability of 17ß-estradiol to stimulate growth of xenografted ER-negative human breast cancer tumors in wild-type and ER-KO SCID mice. We quantified vascularization of tumors, macrophage recruitment to the tumor site by immunocytochemistry, and inflammatory cytokine production.

Results: We show that estrogen treatment of C57BL/6/SCID mice promotes the growth of xenografted ER-negative tumors in wild-type mice and this estrogen-induced tumor growth is abrogated in ER-KO mice. Tumor neovascularization of estrogen-treated mice was unchanged versus control; however, estrogen treatment of the C57BL/6/SCID host suppressed macrophage recruitment to and inflammatory cytokine production at the tumor site.

Conclusions: These data are consistent with estrogen modulation of the inflammatory response as a contributing factor in estrogen-stimulated growth of an ER-negative tumor. This effect on the host innate immune response was mediated by ER-.