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Increased Estrogen Receptor ßcx Expression during Mammary Carcinogenesis

Authors' Affiliations: ¹ Endocrinologie moléculaire et cellulaire des cancers (U540), Institut National de la Santé et de la Recherche Médicale; Departments of ² Pathology and ³ Biostatistics, Cancer Center Val d'Aurelle, Montpellier, France; and ⁴ Department of Medical Nutrition and Biosciences, Karolinska Institute, Huddinge, Sweden

Requests for reprints: Henri Rochefort, Endocrinologie moléculaire et cellulaire des cancers (U540), Institut National de la Sante et de la Recherche Medicale, 60 rue de Navacelles, 34090 Montpellier, France. Phone: 33-467043760; Fax: 33-467540598; E-mail: henri.rochefort{at}montp.inserm.fr.

Identification of proteins that markedly vary during early steps of mammary carcinogenesis may help to understand its pathophysiology and to develop a prevention strategy. The expression of total estrogen receptor ß (ERß) protein and of its COOH-terminally spliced variant ERßcx (or ERß2) was compared in 43 invasive breast cancers and in 39 adjacent normal mammary glands and 26 ductal carcinoma in situ (DCIS). Thirty-six breast cancers were ER positive by radioligand binding assay. The analysis was done by immunohistochemistry on adjacent sections of formalin-fixed, paraffin-embedded tumors using polyclonal anti-ERß 503 IgY and sheep polyclonal ERßcx antibodies that were previously validated. Nuclear staining was quantified using a computerized image analyzer in selected areas of normal and cancer epithelial cells. Total ERß expression was high in normal glands, decreased in DCIS (P = 0.0004), and increased from DCIS to invasive tumors (P = 0.029). In contrast, the ERßcx expression was low in normal glands, increased significantly in DCIS (P = 0.0014), and continued to increase in invasive carcinomas (P = 0.0027) in both ER-positive and ER-negative tumors. This is the first study showing a significant increase of the ERßcx variant protein in DCIS and invasive breast cancer compared with adjacent normal glands. This contrasts with the decrease of the total ERß level in the same patients and indicates different mechanisms to explain these variations during mammary carcinogenesis. It also suggests a role of the ERßcx variant in carcinogenesis opposite to the protective effect of the wild-type ERß1.

Key Words: Estrogen receptor ß • splicing • normal glands • breast cancer • ductal carcinoma in situ • immunohistochemistry • carcinogenesis

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