The Role of Steroid Receptor Coactivator-1 in Breast Cancer
Annual rept. 18 May 2000-17 May 2001
BAYLOR COLL OF MEDICINE HOUSTON TX
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The role of steroid receptor coactivator-1 SRC-1 in breast cancer is primarily a function of i the expression patterns of nuclear receptors NRs and SRC family members in the tumor, and ii their inherent interaction affinities. An outstanding question is the extent to which SRCNR pathways in breast cancer are uncoupled by administration of selective estrogen receptor modulator SERM regimens such as 4-hydroxytamoxifen. An appreciation of the role of SRC-1 and other SRCs in the selective recruitment of NRs during the development of breast cancer is a prerequisite for the design of novel SRMs for treatment of breast cancer. We used BlAcore analysis to monitor interactions between SRCs and His-tagged NRs. Distinct affinities were noted for different NR-coactivator interactions, indicating an interaction preference spectrum for estrogen receptor-alpha ERalpha of SRC-3SRC-1 SRC-2. The interaction of ERalpha with SRC family members was differentially influenced by different SERMs. In all cases, the interaction between ERalpha and SRCs was promoted by 17beta-estradiol and inhibited by 4-hydroxytamoxifen, raloxifene and ICI 182, 780. The interaction kinetics of SRC family members with liganded NRs are consistent with a bipartite model involving a transitional intermediate. By providing accurate measurements of the modulation by SRMs of the interaction between NRs and SRC family members, we have created a model system within which rational design of SERMs for breast cancer treatment can be evaluated in a functional context.
- Medicine and Medical Research