Stephen R Hammes

University of Rochester, Rochester, New York, United States

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Publications (62)305.98 Total impact

  • Allison Light · Stephen R Hammes ·
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    ABSTRACT: Oocyte maturation and cumulus cell expansion depend on LH-mediated upregulation of membrane bound EGF-like ligands, including amphiregulin, epiregulin, and betacellulin. These ligands then trans-activate the EGF receptor (EGFR) after release by matrix metalloproteinases (MMPs). However, direct measurement of released EGF-like ligands or MMPs from granulosa cells has not been formally evaluated, nor has direct identification of responsible MMPs. Here we address these issues by analyzing LH-induced steroidogenesis, which is also MMP- and EGFR-dependent, in freshly isolated mouse primary granulosa cells. We demonstrate a correlation between amphiregulin and epiregulin mRNA induction and steroid production in LH-treated granulosa cells as well as in ovaries of hCG-treated mice. In contrast, LH does not alter Mmp1, Mmp2, Mmp3, Mmp8, Mmp9, or Adam17 mRNA expression. We demonstrate that, in primary mouse granulosa cells, LH triggers release of soluble amphiregulin that correlates with steroid production, both of which are blocked by MMP2/9 inhibition, confirming that MMP2/9 likely regulates LH-induced amphiregulin release and downstream processes. Notably, LH does not alter secretion of MMP2/9 from primary granulosa cells, nor does it modulate MMP activity. These findings indicate that, in the ovary, LH dictates EGFR-mediated processes not by regulating MMPs, but instead by increasing EGF-like ligand availability. In contrast, LH stimulation of primary mouse Leydig cells does not induce EGF-like ligand expression or require MMP2/9 for steroidogenesis, confirming marked differences in LH receptor-induced processes in the testes. Our results suggest that MMP inhibition may be a means of attenuating excess ovarian steroid production in diseases like polycystic ovary syndrome. Copyright 2015 by The Society for the Study of Reproduction.
    Biology of Reproduction 07/2015; 93(3). DOI:10.1095/biolreprod.115.130971 · 3.32 Impact Factor
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    Stephen R. Hammes · Paul J. Davis ·
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    ABSTRACT: The genomic actions of thyroid hormone and steroids depend upon primary interactions of the hormones with their specific nuclear receptor proteins. Formation of nuclear co-activator or co-repressor complexes involving the liganded receptors subsequently result in transcriptional events-either activation or suppression-at genes that are specific targets of thyroid hormone or steroids. Nongenomic actions of thyroid hormone and steroids are in contrast initiated at binding sites on the plasma membrane or in cytoplasm or organelles and do not primarily require formation of intranuclear receptor protein-hormone complexes. Importantly, hormonal actions that begin nongenomically outside the nucleus often culminate in changes in nuclear transcriptional events that are regulated by both traditional intranuclear receptors as well as other nuclear transcription factors. In the case of thyroid hormone, the extranuclear receptor can be the classical "nuclear" thyroid receptor (TR), a TR isoform, or integrin αvβ3. In the case of steroid hormones, the membrane receptor is usually, but not always, the classical "nuclear" steroid receptor. This concept defines the paradigm of overlapping nongenomic and genomic hormone mechanisms of action. Here we review some examples of how extranuclear signaling by thyroid hormone and by estrogens and androgens modulates intranuclear hormone signaling to regulate a number of vital biological processes both in normal physiology and in cancer progression. We also point out that nongenomic actions of thyroid hormone may mimic effects of estrogen in certain tumors. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
    Best Practice & Research: Clinical Endocrinology & Metabolism 04/2015; 145(4). DOI:10.1016/j.beem.2015.04.001 · 4.60 Impact Factor
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    ABSTRACT: We investigated the association of signaling proteins with epidermal growth factor (EGF) receptors (EGFR) using biotinylated EGF bound to streptavidin that is covalently coupled in an ordered array of micron-sized features on silicon surfaces. Using NIH-3T3 cells stably expressing EGFR, we observe concentration of fluorescently labeled receptors and stimulated tyrosine phosphorylation that are spatially confined to the regions of immobilized EGF and quantified by cross-correlation analysis. We observe recruitment of phosphorylated paxillin to activated EGFR at these patterned features, as well as β1-containing integrins that preferentially localize to more peripheral EGF features, as quantified by radial fluorescence analysis. In addition, we detect recruitment of EGFP-Ras, MEK, and phosphorylated Erk to patterned EGF in a process that depends on F-actin and phosphoinositides. These studies reveal and quantify the coformation of multiprotein EGFR signaling complexes at the plasma membrane in response to micropatterned growth factors. Copyright © 2014 Biophysical Society. Published by Elsevier Inc. All rights reserved.
    Biophysical Journal 12/2014; 107(11):2639-51. DOI:10.1016/j.bpj.2014.09.048 · 3.97 Impact Factor
  • Quang V Ton · Stephen R Hammes ·
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    ABSTRACT: Pheochromocytomas are neuroendocrine tumors that commonly lead to excess catecholamine secretion, resulting in elevated blood pressure. In addition to potentiating vasoconstriction, catecholamines promote endothelial dysfunction, as evidenced by elevated markers of endothelial dysfunction, ADMA and sVCAM-1, in patients with pheochromcytoma. Importantly, catecholamine-induced endothelial dysfunction and hypertension may not only be due to catecholamine production by neuroendocrine tumors, as vascular endothelial cells have now been demonstrated to synthesize and secrete catecholamines. This local vascular catecholamine release appears to be triggered by hypoxia. In fact, chronic intermittent hypoxia both in vitro and in vivo leads to stabilization of hypoxic-inducible factors that increase gene expression of catecholamine-synthesizing enzymes. In an effort to target catecholamines as a means of treating hypertension, novel therapeutic options are being explored, including the generation of pharmacophores that mimic the suppressive effects of catestatin on catecholamine release as well as the use of renalase enhancers to increase catecholamine metabolism.
    Current Hypertension Reports 12/2014; 16(12):498. DOI:10.1007/s11906-014-0498-9 · 3.44 Impact Factor
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    Stephen R Hammes ·

    Molecular Endocrinology 11/2014; 28(11):1753-5. DOI:10.1210/me.2014-1311 · 4.02 Impact Factor
  • Stephen R Hammes · Susanne U Miedlich · Aritro Sen ·
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    ABSTRACT: Paxillin is a well-characterized cytoplasmic adaptor protein that is known to play important roles in cytoskeletal rearrangement, cell adhesion, and cell motility. In addition to its structural functions, paxillin has more recently been shown to function as a regulator of cell division-mediating steroid-triggered meiosis in oocytes as well as steroid- and growth factor-induced proliferation in prostate and breast cancer. Paxillin mediates these processes through a conserved pathway that involves both extranuclear (nongenomic) and nuclear (genomic) steroid signaling, as well as both cytoplasmic and nuclear kinase signaling. In fact, paxillin appears to serve as a critical liaison between extranuclear and nuclear signaling in response to multiple stimuli, making it a fascinating molecule to study when trying to determine how growth signals from the membrane lead to important proliferative changes in the nucleus. This chapter outlines recent advances in understanding how paxillin regulates both steroid and growth factor signaling, focusing on the conserved nature of its actions from a frog germ cell to a human cancer cell.
    Methods in Molecular Biology 09/2014; 1204:95-108. DOI:10.1007/978-1-4939-1346-6_9 · 1.29 Impact Factor
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    Stephen R Hammes ·

    Molecular Endocrinology 07/2014; 28(8):me20141209. DOI:10.1210/me.2014-1209 · 4.02 Impact Factor
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    ABSTRACT: Background elevated sympathetic nervous system activity is a salient characteristic of heart failure (HF) progression. It causes pathologic desensitization of β -adrenergic receptors (β -AR), facilitated predominantly through Gβ γ-mediated signaling. The adrenal glands are key contributors to the chronically elevated plasma catecholamine levels observed in HF, where adrenal α2-AR feedback inhibitory function is impaired also through Gβ γ-mediated signaling. Objective we propose simultaneous inhibition of Gβ γ signaling in the heart and the adrenal gland as a novel therapeutic approach for HF. Methods and results we investigated the efficacy of a small molecule Gβ γ inhibitor, gallein, in a clinically relevant, pressure-overload model of HF. Daily gallein treatment (10 mg/kg/day), initiated four weeks following transverse aortic constriction, improved survival and cardiac function, and attenuated cardiac remodeling. Mechanistically, gallein restored β-AR membrane density in cardiomyocytes, attenuated Gβ γ-mediated GRK2-PI3Kγ membrane recruitment, and reduced Akt and GSK-3β phosphorylation. Gallein also reduced circulating plasma catecholamine levels as well as catecholamine production in isolated mouse adrenal glands by restoring adrenal α2-AR feedback inhibition. In human adrenal endocrine tumors (pheochromocytoma), gallein attenuated catecholamine secretion, as well as GRK2 expression and membrane translocation. Conclusions these data suggest small molecule Gβ γ inhibition as a systemic pharmacologic therapy for HF by simultaneously normalizing pathologic adrenergic/Gβ γ signaling in both the heart and the adrenal gland. Our data also suggest important endocrine/cardiovascular interactions and a possible role for small molecule Gβ γ inhibition in treating endocrine tumors such as pheochromocytoma, in addition to HF.
    Journal of the American College of Cardiology 06/2014; 63(23). DOI:10.1016/j.jacc.2014.02.587 · 16.50 Impact Factor
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    Ali Pedram · Mahnaz Razandi · Michael Lewis · Stephen Hammes · Ellis R Levin ·
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    ABSTRACT: Steroid receptors are found in discrete cellular locations, but it is unknown whether extranuclear pools are necessary for normal organ development. To assess this, we developed a point mutant estrogen receptor α (ERα) knockin mouse (C451A) that precludes palmitoylation and membrane trafficking of the steroid receptor in all organs. Homozygous knockin female mice (nuclear-only ERα [NOER]) show loss of rapid signaling that occurs from membrane ERα in wild-type mice. Multiple developmental abnormalities were found, including infertility, relatively hypoplastic uteri, abnormal ovaries, stunted mammary gland ductal development, and abnormal pituitary hormone regulation in NOER mice. These abnormalities were rescued in heterozygous NOER mice that were comparable to wild-type mice. mRNAs implicated in organ development were often poorly stimulated by estrogen only in homozygous NOER mice. We conclude that many organs require membrane ERα and resulting signal transduction to collaborate with nuclear ERα for normal development and function.
    Developmental Cell 05/2014; 29(4):482-90. DOI:10.1016/j.devcel.2014.04.016 · 9.71 Impact Factor
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    ABSTRACT: Although androgen excess is considered detrimental to women's health and fertility, global and ovarian granulosa cell-specific androgen-receptor (AR) knockout mouse models have been used to show that androgen actions through ARs are actually necessary for normal ovarian function and female fertility. Here we describe two AR-mediated pathways in granulosa cells that regulate ovarian follicular development and therefore female fertility. First, we show that androgens attenuate follicular atresia through nuclear and extranuclear signaling pathways by enhancing expression of the microRNA (miR) miR-125b, which in turn suppresses proapoptotic protein expression. Second, we demonstrate that, independent of transcription, androgens enhance follicle-stimulating hormone (FSH) receptor expression, which then augments FSH-mediated follicle growth and development. Interestingly, we find that the scaffold molecule paxillin regulates both processes, making it a critical regulator of AR actions in the ovary. Finally, we report that low doses of exogenous androgens enhance gonadotropin-induced ovulation in mice, further demonstrating the critical role that androgens play in follicular development and fertility. These data may explain reported positive effects of androgens on ovulation rates in women with diminished ovarian reserve. Furthermore, this study demonstrates mechanisms that might contribute to the unregulated follicle growth seen in diseases of excess androgens such as polycystic ovary syndrome.
    Proceedings of the National Academy of Sciences 02/2014; 111(8). DOI:10.1073/pnas.1318978111 · 9.67 Impact Factor
  • Stephen R Hammes ·

    Molecular Endocrinology 01/2014; 28(1):1-2. DOI:10.1210/me.2013-1402 · 4.02 Impact Factor

  • Endocrine Practice 12/2013; DOI:10.4158/EP13410.VV · 2.81 Impact Factor
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    ABSTRACT: Lymphangioleiomyomatosis (LAM) is a rare disease characterized by proliferation of abnormal smooth-muscle cells in the lungs, leading to functional loss and sometimes lung transplantation. While the origin of LAM cells is unknown, several features of LAM provide clues. First, LAM cells contain inactivating mutations in genes encoding Tsc1 or Tsc2, proteins that limit mTORC1 activity. Second, LAM tumors recur after lung transplantation, suggesting a metastatic pathogenesis. Third, LAM is found almost exclusively in women. Finally, LAM shares features with uterine leiomyomas, benign tumors of myometrial cells. From these observations, we proposed that LAM cells might originate from uterine leiomyomas containing Tsc mutations. To test our hypothesis, and to develop mouse models for leiomyoma and LAM, we targeted Tsc2 deletion primarily in uterine cells. In fact, nearly 100% of uteri from uterine-specific Tsc2 knockout mice developed myometrial proliferation and uterine leiomyomas by 12 and 24 weeks, respectively. Myometrial proliferation and mTORC1/S6 activity were abrogated by the mTORC1 inhibitor rapamycin or by elimination of sex steroid production through ovariectomy or aromatase inhibition. In ovariectomized Tsc2 null mice, mTORC1/S6 activity and myometrial growth were restored by estrogen but not progesterone. Thus, even without Tsc2, estrogen appears to be required for myometrial mTORC1/S6 signaling and proliferation. Finally, we found Tsc2 null myometrial tumors in lungs of older Tsc2 uterine-specific knockout females, suggesting that lung LAM-like myometrial lesions may indeed originate from the uterus. This mouse model may improve our understanding of LAM and leiomyomas, and might lead to novel therapeutic strategies for both diseases.
    Molecular Endocrinology 07/2013; 27(9). DOI:10.1210/me.2013-1059 · 4.02 Impact Factor
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    ABSTRACT: Histologically, malignant struma ovarii metastasizes rarely, and only a few cases reported bone metastasis. Here, we describe 2 cases of biologically malignant struma ovarii with pelvic bone metastasis. Case 1 is a 22-year-old female who was found to have a large left ovarian mass during routine prenatal ultrasound. Papillary thyroid cancer arising in struma ovarii was identified after laparoscopic salpingo-oophorectomy. After total thyroidectomy, radioactive iodine whole-body scan revealed extrathyroidal iodine uptake in left anterior pelvis. Subsequent I-131 treatment resolved the pelvic metastasis. Case 2 is a 49-year-old female who was diagnosed with malignant struma ovarii in 1996 and presented in 2007 with pelvic recurrence and extensive left hip metastasis. Treatment with resection of the pelvic tumor, total thyroidectomy, and multiple I-131 ablation led to eventual resolution of the abdominal and left hip foci. In conclusion, we present 2 rare cases of malignant struma ovarii, both with metastasis to the pelvic bone. This report makes pelvic bone the most frequent site for bone metastasis in malignant struma ovarii. It also emphasizes the importance of total thyroidectomy in allowing identification and treatment of bony metastasis with radioactive iodine.
    Gynecologic and Obstetric Investigation 02/2013; 75(2):139-144. DOI:10.1159/000345863 · 1.70 Impact Factor
  • Allison Light · Stephen R Hammes ·
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    ABSTRACT: Steroid production by all three major steroidogenic tissues, the adrenals, testes, and ovaries, is critical for survival and reproduction of all animals. As such, the pathways that regulate steroidogenesis are conserved between these tissues, from the steroidogenic enzymes and cofactors that synthesize steroids, to the intracellular signaling molecules and Gα(s)-coupled receptors that mediate the activity of these enzymes. Recent work has revealed another important conserved pathway in steroidogenesis: crosstalk between membrane G protein-coupled receptors and membrane receptor tyrosine kinases. Luteinizing hormone (LH) or adrencorticotropic hormone (ACTH) binding to their cognate Gα(s)-coupled membrane receptors in the gonads and adrenals, respectively, leads to cAMP-induced trans-activation of the epidermal growth factor (EGF) receptor, followed by activation of Akt and Erk signaling. These kinase signals then activate Steroidogenic Acute Regulatory (StAR) protein, which promotes steroid production. Inhibition of this pathway abrogates both LH- and ACTH-induced steroidogenesis. Interestingly, LH-induced transactivation of the EGF receptor in the ovary uniquely requires matrix metalloproteinase-mediated release of EGF receptor ligands, and inhibition of these proteases blocks LH-induced steroidogenesis. Given this unique need for matrix metalloproteinases in ovarian steroidogenesis, MMP inhibition may prove to be useful when treating diseases of excess ovarian steroid production, such as polycystic ovary syndrome.
    Steroids 02/2013; 78(6). DOI:10.1016/j.steroids.2012.12.016 · 2.64 Impact Factor
  • Stephen Hammes · Martin Kelly · Joyce Slingerland ·

    Steroids 01/2013; 78(6). DOI:10.1016/j.steroids.2013.01.001 · 2.64 Impact Factor
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    Stephen R Hammes · Vera P Krymskaya ·
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    ABSTRACT: Pulmonary lymphangioleiomyomatosis (LAM) is a rare disease found almost exclusively in women that is characterized by neoplastic growth of atypical smooth muscle-like cells in the lung, destruction of lung parenchyma, and obstruction of lymphatics. These processes lead to the formation of lung cysts, rupture of which results in spontaneous pneumothorax. Progression of LAM often results in loss of pulmonary function and death. LAM affects predominantly women of childbearing age and is exacerbated by pregnancy. The only proven treatment for LAM is lung transplantation, and even then LAM cells will often return to the transplanted lung. However, methodical and targeted approaches toward understanding LAM pathophysiology have led to the discovery of new potential therapeutic avenues. For example, the mutational inactivation of tumor suppressor complex genes tuberous sclerosis complex 1 or tuberous sclerosis complex 2 has been shown to be present in lung LAM cells. These mutations occur sporadically or in association with inherited hamartoma syndrome tuberous sclerosis (TSC). Since TSC genes function as negative regulators of the mammalian target of rapamycin, a major controller of cell growth, metabolism, and survival, rapamycin analogs have recently been used to treat LAM patients with promising results. Similarly, studies focusing on the importance of estrogen in LAM progression have suggested that anti-estrogen therapy might prove to be an alternative means of treating LAM. This minireview summarizes recent progress in understanding LAM pathophysiology, including the latest preclinical and clinical studies, and insights regarding the role of hormones in LAM.
    Hormones and Cancer 11/2012; 4(2). DOI:10.1007/s12672-012-0128-4 · 0.02 Impact Factor
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    ABSTRACT: In prostate cancer, the signals that drive cell proliferation change as tumors progress from castration-sensitive (androgen-dominant) to castration-resistant states. While the mechanisms underlying this change remain uncertain, characterization of common signaling components that regulate both stages of prostate cancer proliferation is important for developing effective treatment strategies. Here, we demonstrate that paxillin, a known cytoplasmic adaptor protein, regulates both androgen- and EGF-induced nuclear signaling. We show that androgen and EGF promoted MAPK-dependent phosphorylation of paxillin, resulting in nuclear translocation of paxillin. We found nuclear paxillin could then associate with androgen-stimulated androgen receptor (AR). This complex bound AR-sensitive promoters, retaining AR within the nucleus and regulating AR-mediated transcription. Nuclear paxillin also complexed with ERK and ELK1, mediating c-FOS and cyclin D1 expression; this was followed by proliferation. Thus, paxillin is a liaison between extranuclear MAPK signaling and nuclear transcription in response to androgens and growth factors, making it a potential regulator of both castration-sensitive and castration-resistant prostate cancer. Accordingly, paxillin was required for normal growth of human prostate cancer cell xenografts, and its expression was elevated in human prostate cancer tissue microarrays. Paxillin is therefore a potential biomarker for prostate cancer proliferation and a possible therapeutic target for prostate cancer treatment.
    The Journal of clinical investigation 06/2012; 122(7):2469-81. DOI:10.1172/JCI62044 · 13.22 Impact Factor
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    Melanie J Grubisha · M E Cifuentes · Stephen R Hammes · Donald B Defranco ·
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    ABSTRACT: The tumor microenvironment plays a critical role in supporting cancer cells particularly as they disengage from limitations on their growth and motility imposed by surrounding nonreactive stromal cells. We show here that stromal-derived androgenic precursors are metabolized by DU145 human prostate cancer (PCa) cells to generate ligands for estrogen receptor-β, which act to limit their motility through transcriptional regulation of E-cadherin. Although primary human PCa-associated fibroblasts and the human WPMY-1-reactive prostate stromal cell line maintain this inherent estrogen receptor (ER)β-dependent motility inhibitor activity, they are subverted by TGF-β1 pro-oxidant signals derived from cocultured DU145 PCa cells. Specifically, stromal-produced H(2)O(2), which requires Cox-2, acts as a second paracrine factor to inhibit ERβ activity in adjacent DU145 cells. Chromatin immunoprecipitation analysis reveals that ERβ recruitment to the E-cadherin promoter is inhibited when H(2)O(2) is present. Both neutralization of H(2)O(2) with catalase and prevention of its production by silencing Cox-2 expression in stromal cells restore the motility-suppression activity of stromal-derived ERβ ligand precursors. These data suggest that reactive stromal cells may still have a capacity to limit cancer cell motility through a local endocrine network but must be protected from pro-oxidant signals triggered by cancer cell-derived TGF-β1 to exhibit this cancer-suppressive function.
    Molecular Endocrinology 05/2012; 26(6):940-54. DOI:10.1210/me.2011-1371 · 4.02 Impact Factor
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    ABSTRACT: The ability of 17β-estradiol (E2) to regulate the proliferation of prostate cancer (PCa) cells in the absence of androgen is poorly understood. Here, we show the predominant estrogen receptor (ER) isoform expressed in PCa specimens and cell lines is ERβ. Our data indicate that E2 induces the formation of a complex between androgen receptor (AR), ERβ, and a proline-, glutamic acid-, and leucine-rich cofactor protein 1 (PELP1) in PCa cells. This protein complex is formed on AR's cognate DNA-responsive elements on the promoter in response to E2. Formation of this complex enables the transcription of AR-responsive genes in response to E2. Knockdown of PELP1, AR, or ERβ blocks the assembly of this complex, blocks E2-induced genomic activation of AR-regulated genes, and blocks E2-stimulated proliferation of PCa cells. Overall, this study shows that PELP1 may enable E2-induced AR signaling by forming a protein complex between AR, ERβ, and PELP1 on the DNA, leading to the proliferation of PCa cells in the absence of androgen. PELP1 may bridge the signal between E2 bound to ERβ and AR and thus allow for cross talk between these steroid receptors. These data suggest a novel mechanism of AR activation in the absence of androgens in PCa cells. Our data indicate that disruption of the complex between AR and PELP1 may be a viable therapeutic strategy in advanced PCa.
    Molecular Endocrinology 03/2012; 26(4):550-61. DOI:10.1210/me.2011-1101 · 4.02 Impact Factor

Publication Stats

2k Citations
305.98 Total Impact Points


  • 2010-2015
    • University of Rochester
      • • Department of Medicine
      • • Division of Hospital Medicine
      • • Division of Endocrinology and Metabolism
      Rochester, New York, United States
  • 2010-2014
    • University Center Rochester
      • Department of Medicine
      Рочестер, Minnesota, United States
  • 2001-2008
    • University of Texas Southwestern Medical Center
      • • Department of Developmental Biology
      • • Department of Internal Medicine
      • • Department of Pharmacology
      • • Division of Endocrinology
      Dallas, Texas, United States
    • University of Texas at Dallas
      Richardson, Texas, United States
  • 2007
    • University of Pittsburgh
      Pittsburgh, Pennsylvania, United States
  • 1999
    • Cardiovascular Research Foundation
      New York, New York, United States
  • 1998
    • University of California, San Francisco
      • Department of Medicine
      San Francisco, California, United States