D S Hunter

University of Texas MD Anderson Cancer Center, Houston, Texas, United States

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Publications (3)16.96 Total impact

  • GA Finlay · D S Hunter · C L Walker · K E Paulson · B L Fanburg
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    ABSTRACT: Mechanisms that regulate the growth response to estrogen (17beta-estradiol, E2) are poorly understood. Recently, loss of function of the tuberous sclerosis complex 2 (TSC2) gene has been associated with E2-related conditions that are characterized by benign cellular proliferation. We examined the growth response to E2 in vascular smooth muscle cells (VSMCs) that possess wild-type TSC2 and compared them with ELT-3 smooth muscle cells that do not express TSC2. In TSC2-expressing VSMCs, growth inhibition in response to E2 was associated with downregulation of platelet-derived growth factor (PDGF), PDGF receptor (PDGFR), and limited activation of extracellular signal-regulated kinase (ERK). In contrast, the growth-promoting effect of E2 in TSC2-null ELT-3 cells was associated with induction of PDGF, robust phosphorylation of PDGFR, and sustained activation of ERK. Furthermore, in ELT-3 cells, cellular growth and ERK activation by E2 were inhibited by the PDGFR inhibitor tyrphostin AG 17 and by PDGF-neutralizing antibody. These results demonstrate that autocrine production of PDGF and augmentation of the ERK pathway leads to estrogen-induced cellular proliferation in TSC2-null cells, a pathway that was downregulated in cells that express TSC2. Understanding the mechanisms that regulate the diverse responses to the steroid hormone estrogen could lead to novel approaches to the treatment of estrogen-related diseases that are characterized by aberrant cell proliferation.
    AJP Cell Physiology 09/2003; 285(2):C409-18. DOI:10.1152/ajpcell.00482.2002 · 3.78 Impact Factor
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    L C Hodges · J S Bergerson · D S Hunter · C L Walker
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    ABSTRACT: Although benign, uterine leiomyomas occur with high frequency and significant morbidity in reproductive-age women, and they present a significant health problem. Leiomyomas develop in the uterine myometrium and are sensitive to ovarian hormones, making them potential target sites for endocrine disruptors. Here we utilize cell lines derived from rat uterine leiomyomas to determine if a panel of 7 organochlorine pesticides have potential agonist activity in myometrial cells using cellular and molecular in vitro assays. The organochlorine pesticides investigated have been previously characterized as having agonist activity in other hormonally responsive tissues, but their effects have not been studied in uterine myometrial cells. In Eker rat leiomyoma-derived cells, HPTE, kepone, and the alpha isomer of endosulfan stimulated proliferation, an effect dampened by the antiestrogen ICI 182,780. In addition, these compounds stimulated transcription of the vitellogenin estrogen-response element via the ER in a transcriptional reporter gene assay and induced the expression of an endogenous estrogen-responsive gene, the progesterone receptor (PR). This contrasted with the agonist profile of methoxychlor, dieldrin, toxaphene, and endosulfan-beta. These compounds, unable to stimulate proliferation of uterine leiomyoma cells, did exhibit agonistic activity in these cells at the transcriptional level in the estrogen-sensitive reporter gene assay, and they were also able to upregulate PR message. These data demonstrate that organochlorine pesticides act as estrogen receptor agonists in Eker rat uterine myometrial cells, and they indicate a need for further investigation of the potential tissue-specific agonist activity of these pesticides and their role in the pathogenesis of uterine leiomyoma.
    Toxicological Sciences 05/2000; 54(2):355-64. DOI:10.1093/toxsci/54.2.355 · 3.85 Impact Factor
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    ABSTRACT: The possible contribution of endocrine disrupters to human disease, particularly those compounds that modulate the estrogen receptor (ER), has recently drawn considerable attention. The tissue specificity of effects mediated by the ER is well recognized, although the mechanism of this specificity is not understood sufficiently to predict the effects of a particular ligand in different target tissues. Although the divergence of ER-mediated effects in the breast, bone, and uterine endometrium has been described, a frequently overlooked site of estrogen action is the smooth muscle of the uterus. The uterine myometrium is the tissue of origin of an extremely common hormone-responsive tumor, uterine leiomyoma, a tumor with a significant impact on women's health and a possible environmental influence. This report describes an in vitro/in vivo system for identifying the effects of ER ligands in the myometrium and elucidating their mechanism of action. Several natural and synthetic xenoestrogens were evaluated at the cellular and molecular level for their ability to mimic estrogen action in uterine myometrial tissues. Diethylstilbestrol, coumestrol, genistein, naringenin, and endosulfan were able to activate the AF2 function of the ER in vitro and demonstrated agonist activity in estrogen-responsive myometrial cells, as determined by induction of proliferation and increased message levels of progesterone receptor. Compounds that could not activate AF2 function (4-hydroxy-tamoxifen, LY117018, and LY317783) did not act as estrogen agonists. For agonists, rank order of potency was predicted by receptor affinity; however, endosulfan displayed a surprising degree of activity, despite negligible receptor binding. Additionally, diethylstilbestrol and tamoxifen demonstrated prototypical agonist and antagonist effects, respectively, in the intact myometrium of sexually mature rats. The results presented here suggest that some exogenous ER ligands may mimic the effects of endogenous estrogens on uterine leiomyoma and may contribute to a complex hormonal milieu that impacts both normal and neoplastic myometrium.
    Cancer Research 08/1999; 59(13):3090-9. · 9.33 Impact Factor

Publication Stats

153 Citations
16.96 Total Impact Points


  • 1999–2000
    • University of Texas MD Anderson Cancer Center
      • Science Park - Research Division
      Houston, Texas, United States