MINISYMPOSIUM IV. Coactivators in Steroid Hormone Action and Reproductive Physiology
11:00 AM-12:30 PM
Grand Ballroom VI
Chair: McCarthy, Margaret1, 1
(M11) THE SRC GENE FAMILY IS REQUIRED FOR NORMAL DEVELOPMENT AND REPRODUCTION.
Xu, Jianming1, Kuang, Shao-Qing1, Yoshida-Komiya, Hiromi1, Nishihara, Eijun1, Liao, Lan1, DeMayo, Francesco1, O'Malley, Bert1, 1 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
ABSTRACT- Steroid hormones regulate many cellular events in development, homeostasis, reproduction and tumorigenesis through binding to their cognate steroid receptors (SRs). The ligand-activated SRs rely on recruitment of multiple classes of coactivators to enhance target gene transcription. Among these coactivators, the three homologous members of the steroid receptor coactivator (SRC) family have been demonstrated to interact with SRs in a ligand-dependent manner and to strongly coactivate target gene transcription by SRs in a variety of in vitro and ex vivo experiments. In order to investigate their in vivo functions, we generated SRC-1 and SRC-3 (also known as p/CIP, RAC3, AIB1, ACTR or TRAM-1) knockout mouse lines. Although both male and female SRC-1 knockout mice were viable and fertile, steroid hormone target organs such as uterus, mammary gland, testis and prostate exhibited a decrease in growth and development in response to steroid hormones. These results suggest that SRC-1 mediates partial steroid hormone responses in vivo and that loss of its coactivator function results in partial resistance to multiple steroid hormones. In addition, expression of RNA for SRC-2 (also known as GRIP1 or TIF2) was increased in the SRC-1 knockout mice, indicating a possible compensation for the loss of SRC-1 function in certain hormone target tissues. Transcriptional activity of the SRC-3 gene promoter in mice was mainly identified in the oocytes, mammary glands, brain, smooth muscle, hepatocytes and vaginal epithelium. Both male and female SRC-3 knockout mice exhibited growth retardation with lower levels of IGF-1. The male SRC-3 knockout mice showed no obvious reproductive defect. The female SRC-3 knockout mice exhibited developmental delays in puberty and mammary gland ductal growth, which were accompanied with lower levels of estrogen. Furthermore, the mammary ductal branching and alveolar formation in response to estrogen and progesterone treatment were significantly attenuated in adult female SRC-3 knockout mice. Since SRC-3 was a highly amplified and overexpressed SR coactivator in breast tumors, we also evaluated the role of SRC-3 in breast cancer by comparing the MMTV-h-ras-induced tumorigenesis between wild type and SRC-3 knockout mice. We found the loss of SRC-3 strongly suppresses breast cancer initiation and progression. Additionally, female SRC-3 knockout mice exhibited a significant decrease in reproductive function, as evidenced by longer estrous cycling time, reduced ovulation capability, lower pregnancy frequency after successful mating, less number of pups per litter, and early termination of reproductive function. These results demonstrate that SRC-3 is required for normal growth, development and reproduction. Targeting of the SRC-3 function may be a useful approach to inhibit breast cancer initiation and progression. Importantly, the phenotypical differences of SRC-1 and SRC-3 knockout mice suggest that members of the SRC family play divers biological roles although their functions may be partially overlapping.
KEY WORDS: steroid receptor, coactivator, knockout mice, breast cancer