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Normal Breast Tissue Implanted into Athymic Nude Mice Identifies Biomarkers of the Effects of Human Pregnancy Levels of Estrogen

Authors' Affiliations: ¹ Breast Biology Group and ² Medical Oncology, School of Cancer and Imaging Sciences, Paterson Institute for Cancer Research, University of Manchester, Manchester, United Kingdom; ³ Cancer and Infection Research Area, AstraZeneca, Macclesfield, Cheshire, United Kingdom; and ⁴ Breakthrough Research Unit, Edinburgh Cancer Research Centre, Western General Hospital, Edinburgh, United Kingdom

Requests for reprints: Robert B. Clarke, Breast Biology Group, School of Cancer and Imaging Sciences, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, Manchester M20 4B, United Kingdom. Phone: 44-161-446-3210; Fax: 44-161-446-3220; E-mail: robert.clarke{at}manchester.ac.uk.

We have generated a novel model system for the study of estrogen intervention in normal breast tissue. Nulliparous human breast tissue was implanted into immunocompromised nude mice and treated with high-dose estrogen to simulate the effects of pregnancy. Treatment of mice with human mid-pregnancy levels of 17β-estradiol for a period of 4 weeks was followed by 4 weeks of withdrawal to mimic involution. Gene expression in the xenograft tissue was then analyzed by real-time reverse transcription-PCR to identify differences between treated and control tissues. Ten genes previously identified as altered by pregnancy in rodent models were found to be differentially expressed in human breast tissue with a 1.8-fold up-regulation of CDC42, TGFβ₃, DCN, KRT14, LTF, and AREG and a 0.7-fold down-regulation of STAT1, CTGF, IGF1, and VAMP1. Immunohistochemical analysis of archival paraffin-embedded adult premenopausal human breast tissue specimens identified a significantly lower level of expression of STAT1 (P < 0.05, Mann-Whitney U test) in parous compared with age-matched nulliparous tissue (median of 24% compared with 42% epithelial cells positive). We conclude that many of the pregnancy-induced breast cancer–protective changes observed in rodent models also occur in human breast tissue following intervention using human pregnancy levels of estrogen and that STAT1 expression is a potential biomarker of parity-induced breast cancer protection in the human breast.

Key Words: xenograft • parity • prevention

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