MAJOR MOLECULAR-WEIGHT HETEROGENEITY OF ESTROGEN-RECEPTOR FROM BREAST-CANCER IS NOT RELATED TO NEOPLASIA

Recent investigation from our laboratory revealed that the estrogen re ceptor (ER) from breast cancer is characterized by a high molecular we ight polymorphism: SDS-polyacrylamide gel electrophoresis of [H-3]-tam oxifen aziridine ([H-3]-TAZ) labeled cytosols usually display several bands corresponding to the native receptor (67 KDa) and lower molecula r cleavage products. High frequency of such altered receptors was conf irmed here by size exclusion FPLC of [I-125]-E(2) labeled cytosols fro m a series of 98 breast cancers: on the average, 60% of the ER molecul es were strongly degraded (Mr less than or equal to 37 KDa). The absen ce of transcriptional activating domains (ABC domains) in such recepto rs was further demonstrated by assessing their ability to bind to hydr oxylapatite (HAP). Thus, in presence of 500 mM KCl, 55% of ERs from an other series of 54 cytosols failed to strongly adsorb to this phosphoc alcic matrix, a characteristic property of receptors without exposed A BC domains. Finally, [H-3]-TAZ labeled cytosols from normal uterine ti ssue and MCF-7 human breast cancer cells growing in nude mice displaye d identical multibands electrophoretic patterns revealing in both case s native and cleaved receptors. Since latter receptor forms were never detected in MCF-7 cells growing in monolayer culture, we put forward the hypothesis that they were produced under the action of proteolytic enzymes acting at the time of tissue processing. Hence, most of the t runcated receptors detected in human breast cancer cytosols should not be markers of malignancy.