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  1. Article ; Online: GH-dependent growth of experimentally induced carcinomas in vivo.

    Marker, Paul C / Unterberger, Christopher J / Swanson, Steven M

    Endocrine-related cancer

    2023  Volume 30, Issue 5

    Abstract: Interest in investigating the role of the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis in the initiation and progression of experimentally induced carcinomas has arisen due to several observations in the human population. First, subjects ...

    Abstract Interest in investigating the role of the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis in the initiation and progression of experimentally induced carcinomas has arisen due to several observations in the human population. First, subjects with Laron syndrome who lack GH signaling have significantly lower rates of cancer than people who have normal GH signaling. Second, epidemiologic studies have found strong associations between elevated circulating IGF-1 and the incidence of several common cancers. Third, women who bear children early in life have a dramatically reduced risk of developing breast cancer, which may be due to differences in hormone levels including GH. These observations have motivated multiple studies that have experimentally altered activity of the GH/IGF-1 axis in the context of experimental carcinoma models in mice and rats. Most of these studies have utilized carcinoma models for four organ systems that are also frequent sites of carcinomas in humans: the mammary gland, prostate gland, liver, and colon. This review focuses on these studies and describes some of the most common genetic models used to alter the activity of the GH/IGF-1 axis in experimentally induced carcinomas. A recurring theme that emerges from these studies is that manipulations that reduce the activity of GH or mediators of GH action also inhibit carcinogenesis in multiple model systems.
    MeSH term(s) Male ; Female ; Rats ; Mice ; Humans ; Animals ; Growth Hormone ; Insulin-Like Growth Factor I/metabolism ; Neoplasm Recurrence, Local ; Human Growth Hormone ; Carcinoma
    Chemical Substances Growth Hormone (9002-72-6) ; Insulin-Like Growth Factor I (67763-96-6) ; Human Growth Hormone (12629-01-5)
    Language English
    Publishing date 2023-03-29
    Publishing country England
    Document type Review ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1218450-0
    ISSN 1479-6821 ; 1351-0088
    ISSN (online) 1479-6821
    ISSN 1351-0088
    DOI 10.1530/ERC-22-0403
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 4192: Show issues Location:
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  2. Article ; Online: Mammary Tumor Growth and Proliferation Are Dependent on Growth Hormone in Female SV40 C3(1) T-Antigen Mice.

    Unterberger, Christopher J / McGregor, Stephanie M / Kopchick, John J / Swanson, Steven M / Marker, Paul C

    Endocrinology

    2022  Volume 164, Issue 2

    Abstract: Female SV40 C3(1) T-antigen (C3(1)/TAg) transgenic mice develop mammary tumors that are molecularly similar to human basal-like breast cancers with 100% incidence at 16 weeks of age. To determine the requirement for growth hormone (GH) signaling in these ...

    Abstract Female SV40 C3(1) T-antigen (C3(1)/TAg) transgenic mice develop mammary tumors that are molecularly similar to human basal-like breast cancers with 100% incidence at 16 weeks of age. To determine the requirement for growth hormone (GH) signaling in these tumors, genetic crosses were used to create cohorts of female mice that were homozygous for a floxed growth hormone receptor (Ghr) gene and carried one copy each of the Rosa-Cre-ERT2 transgene and the C3(1)/TAg transgene (Ghrflox/flox; Rosa-Cre-ERT2; C3(1)/TAg+/0 mice). When the largest mammary tumor reached 200 mm3, mice were treated with tamoxifen to delete Ghr or with vehicle as a control. An additional group of Ghrflox/flox; C3(1)/TAg+/0 mice were also treated with tamoxifen when the largest mammary tumor reached 200 mm3 as a control for the effects of tamoxifen. After 3 weeks, tumors in mice in which Ghr was deleted began to shrink while vehicle and tamoxifen treatment control mouse tumors continued to grow. Pathological analysis of tumors revealed similar growth patterns and varying levels of necrosis throughout all groups. A decrease in cancer cell proliferation in Ghr-/- tumors relative to controls was observed as measured by Ki67 immunohistochemistry labeling index. These data suggest that even established C3(1)/TAg mammary tumors are dependent on the GH/IGF-1 axis.
    MeSH term(s) Animals ; Female ; Humans ; Mice ; Antigens, Polyomavirus Transforming/genetics ; Cell Proliferation ; Growth Hormone/metabolism ; Mammary Neoplasms, Experimental/metabolism ; Mammary Neoplasms, Experimental/pathology ; Mice, Transgenic ; Tamoxifen/pharmacology ; Receptors, Somatostatin/genetics
    Chemical Substances Antigens, Polyomavirus Transforming ; Growth Hormone (9002-72-6) ; Tamoxifen (094ZI81Y45) ; Receptors, Somatostatin
    Language English
    Publishing date 2022-09-28
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 427856-2
    ISSN 1945-7170 ; 0013-7227
    ISSN (online) 1945-7170
    ISSN 0013-7227
    DOI 10.1210/endocr/bqac174
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Oligo(Lactic Acid)

    Repp, Lauren / Unterberger, Christopher J / Ye, Zhengqing / Feltenberger, John B / Swanson, Steven M / Marker, Paul C / Kwon, Glen S

    Nanomaterials (Basel, Switzerland)

    2021  Volume 11, Issue 10

    Abstract: Docetaxel (DTX) is among the most frequently prescribed chemotherapy drugs and has recently been shown to extend survival in advanced prostate cancer patients. However, the poor water solubility of DTX prevents full exploitation of this potent anticancer ...

    Abstract Docetaxel (DTX) is among the most frequently prescribed chemotherapy drugs and has recently been shown to extend survival in advanced prostate cancer patients. However, the poor water solubility of DTX prevents full exploitation of this potent anticancer drug. The current marketed formulation, Taxotere
    Language English
    Publishing date 2021-10-17
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2662255-5
    ISSN 2079-4991
    ISSN 2079-4991
    DOI 10.3390/nano11102745
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Mammary Tumors Growing in the Absence of Growth Hormone Are More Sensitive to Doxorubicin Than Wild-Type Tumors.

    Lantvit, Daniel D / Unterberger, Christopher J / Lazar, Michelle / Arneson, Paige D / Longhurst, Colin A / Swanson, Steven M / Marker, Paul C

    Endocrinology

    2021  Volume 162, Issue 4

    Abstract: Previously, we reported that N-methyl-N-nitrosourea (MNU)-induced mammary tumors could be established in mutant spontaneous dwarf rats (SDRs), which lack endogenous growth hormone (GH) by supplementing with exogenous GH, and almost all such tumors ... ...

    Abstract Previously, we reported that N-methyl-N-nitrosourea (MNU)-induced mammary tumors could be established in mutant spontaneous dwarf rats (SDRs), which lack endogenous growth hormone (GH) by supplementing with exogenous GH, and almost all such tumors regressed upon GH withdrawal. When the highly inbred SDR line was outcrossed to wild-type (WT) Sprague-Dawley rats, MNU-induced mammary tumors could still be established in resulting outbred SDRs by supplementing with exogenous GH. However, unlike tumors in inbred SDRs, 65% of mammary tumors established in outbred SDRs continued growth after GH withdrawal. We further tested whether these tumors were more sensitive to doxorubicin than their WT counterparts. To accomplish this, MNU-induced mammary tumors were established in WT rats and in SDRs supplemented with exogenous GH. Once mammary tumors reached 1 cm3 in size, exogenous GH was withdrawn from SDRs, and the subset that harbored tumors that continued or resumed growth in the absence of GH were selected for doxorubicin treatment. Doxorubicin was then administered in 6 injections over 2 weeks at 2.5 mg/kg or 1.25 mg/kg for both the WT and SDR groups. The SDR mammary tumors that had been growing in the absence of GH regressed at both doxorubicin doses while WT tumors continued to grow robustly. The regression of SDR mammary tumors treated with 1.25 mg/kg doxorubicin was accompanied by reduced proliferation and dramatically higher apoptosis relative to the WT mammary tumors treated with 1.25 mg/kg doxorubicin. These data suggest that downregulating GH signaling may decrease the doxorubicin dose necessary to effectively treat breast cancer.
    MeSH term(s) Animals ; Antineoplastic Agents/administration & dosage ; Apoptosis/drug effects ; Breast Neoplasms/drug therapy ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Breast Neoplasms/physiopathology ; Cell Proliferation/drug effects ; Doxorubicin/administration & dosage ; Female ; Growth Hormone/metabolism ; Humans ; Rats, Sprague-Dawley ; Rats
    Chemical Substances Antineoplastic Agents ; Doxorubicin (80168379AG) ; Growth Hormone (9002-72-6)
    Language English
    Publishing date 2021-01-20
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 427856-2
    ISSN 1945-7170 ; 0013-7227
    ISSN (online) 1945-7170
    ISSN 0013-7227
    DOI 10.1210/endocr/bqab013
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: GH Action in Prostate Cancer Cells Promotes Proliferation, Limits Apoptosis, and Regulates Cancer-related Gene Expression.

    Unterberger, Christopher J / Maklakova, Vilena I / Lazar, Michelle / Arneson, Paige D / Mcilwain, Sean J / Tsourkas, Philippos K / Hu, Rong / Kopchick, John J / Swanson, Steven M / Marker, Paul C

    Endocrinology

    2022  Volume 163, Issue 5

    Abstract: Previous studies investigating the effects of blocking the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis in prostate cancer found no effects of the growth hormone receptor (GHR) antagonist, pegvisomant, on the growth of grafted human ... ...

    Abstract Previous studies investigating the effects of blocking the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis in prostate cancer found no effects of the growth hormone receptor (GHR) antagonist, pegvisomant, on the growth of grafted human prostate cancer cells in vivo. However, human GHR is not activated by mouse GH, so direct actions of GH on prostate cancer cells were not evaluated in this context. The present study addresses the species specificity of GH-GHR activity by investigating GH actions in prostate cancer cell lines derived from a mouse Pten-deletion model. In vitro cell growth was stimulated by GH and reduced by pegvisomant. These in vitro GH effects were mediated at least in part by the activation of JAK2 and STAT5. When Pten-mutant cells were grown as xenografts in mice, pegvisomant treatment dramatically reduced xenograft size, and this was accompanied by decreased proliferation and increased apoptosis. RNA sequencing of xenografts identified 1765 genes upregulated and 953 genes downregulated in response to pegvisomant, including many genes previously implicated as cancer drivers. Further evaluation of a selected subset of these genes via quantitative reverse transcription-polymerase chain reaction determined that some genes exhibited similar regulation by pegvisomant in prostate cancer cells whether treatment was in vivo or in vitro, indicating direct regulation by GH via GHR activation in prostate cancer cells, whereas other genes responded to pegvisomant only in vivo, suggesting indirect regulation by pegvisomant effects on the host endocrine environment. Similar results were observed for a prostate cancer cell line derived from the mouse transgenic adenocarcinoma of the mouse prostate (TRAMP) model.
    MeSH term(s) Animals ; Apoptosis/genetics ; Cell Proliferation/genetics ; Gene Expression ; Growth Hormone/genetics ; Human Growth Hormone/genetics ; Human Growth Hormone/pharmacology ; Humans ; Insulin-Like Growth Factor I/metabolism ; Male ; Mice ; Prostate/metabolism ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/metabolism ; Receptors, Somatotropin/genetics ; Receptors, Somatotropin/metabolism
    Chemical Substances Receptors, Somatotropin ; Human Growth Hormone (12629-01-5) ; Insulin-Like Growth Factor I (67763-96-6) ; Growth Hormone (9002-72-6)
    Language English
    Publishing date 2022-04-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 427856-2
    ISSN 1945-7170 ; 0013-7227
    ISSN (online) 1945-7170
    ISSN 0013-7227
    DOI 10.1210/endocr/bqac031
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Conditional gene regulation models demonstrate a pro-proliferative role for growth hormone receptor in prostate cancer.

    Unterberger, Christopher J / McIlwain, Sean J / Tsourkas, Philippos K / Maklakova, Vilena I / Prince, Jordyn L / Onesti, Abigail / Hu, Rong / Kopchick, John J / Swanson, Steven M / Marker, Paul C

    The Prostate

    2022  Volume 83, Issue 5, Page(s) 416–429

    Abstract: Background: Humans with inactivating mutations in growth hormone receptor (GHR) have lower rates of cancer, including prostate cancer. Similarly, mice with inactivating Ghr mutations are protected from prostatic intraepithelial neoplasia in the C3(1)/ ... ...

    Abstract Background: Humans with inactivating mutations in growth hormone receptor (GHR) have lower rates of cancer, including prostate cancer. Similarly, mice with inactivating Ghr mutations are protected from prostatic intraepithelial neoplasia in the C3(1)/TAg prostate cancer model. However, gaps in clinical relevance in those models persist. The current study addresses these gaps and the ongoing role of Ghr in prostate cancer using loss-of-function and gain-of-function models.
    Methods: Conditional Ghr inactivation was achieved in the C3(1)/TAg model by employing a tamoxifen-inducible Cre and a prostate-specific Cre. In parallel, a transgenic GH antagonist was also used. Pathology, proliferation, and gene expression of 6-month old mouse prostates were assessed. Analysis of The Cancer Genome Atlas data was conducted to identify GHR overexpression in a subset of human prostate cancers. Ghr overexpression was modeled in PTEN-P2 and TRAMP-C2 mouse prostate cancer cells using stable transfectants. The growth, proliferation, and gene expression effects of Ghr overexpression was assessed in vitro and in vivo.
    Results: Loss-of-function for Ghr globally or in prostatic epithelial cells reduced proliferation and stratification of the prostatic epithelium in the C3(1)/TAg model. Genes and gene sets involved in the immune system and tumorigenesis, for example, were dysregulated upon global Ghr disruption. Analysis of The Cancer Genome Atlas revealed higher GHR expression in human prostate cancers with ERG-fusion genes or ETV1-fusion genes. Modeling the GHR overexpression observed in these human prostate cancers by overexpressing Ghr in mouse prostate cancer cells with mutant Pten or T-antigen driver genes increased proliferation of prostate cancer cells in vitro and in vivo. Ghr overexpression regulated the expression of multiple genes oppositely to Ghr loss-of-function models.
    Conclusions: Loss-of-function and gain-of-function Ghr models, including prostatic epithelial cell specific alterations in Ghr, altered proliferation, and gene expression. These data suggest that changes in GHR activity in human prostatic epithelial cells play a role in proliferation and gene regulation in prostate cancer, suggesting the potential for disrupting GH signaling, for example by the FDA approved GH antagonist pegvisomant, may be beneficial in treating prostate cancer.
    MeSH term(s) Animals ; Humans ; Infant ; Male ; Mice ; Gene Expression Regulation ; Growth Hormone/genetics ; Growth Hormone/metabolism ; Prostate/pathology ; Prostatic Neoplasms/pathology ; Receptors, Somatotropin/genetics ; Receptors, Somatotropin/metabolism
    Chemical Substances Growth Hormone (9002-72-6) ; Receptors, Somatotropin ; somatotropin-binding protein (W06KFL3RDT)
    Language English
    Publishing date 2022-12-22
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 604707-5
    ISSN 1097-0045 ; 0270-4137
    ISSN (online) 1097-0045
    ISSN 0270-4137
    DOI 10.1002/pros.24474
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1608: Show issues Location:
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  7. Article ; Online: Prostate epithelial-specific expression of activated PI3K drives stromal collagen production and accumulation.

    Wegner, Kyle A / Mueller, Brett R / Unterberger, Christopher J / Avila, Enrique J / Ruetten, Hannah / Turco, Anne E / Oakes, Steven R / Girardi, Nicholas M / Halberg, Richard B / Swanson, Steven M / Marker, Paul C / Vezina, Chad M

    The Journal of pathology

    2019  Volume 250, Issue 2, Page(s) 231–242

    Abstract: We genetically engineered expression of an activated form of P110 alpha, the catalytic subunit of PI3K, in mouse prostate epithelium to create a mouse model of direct PI3K activation (Pbsn-cre4Prb; ... ...

    Abstract We genetically engineered expression of an activated form of P110 alpha, the catalytic subunit of PI3K, in mouse prostate epithelium to create a mouse model of direct PI3K activation (Pbsn-cre4Prb;PI3K
    MeSH term(s) Aging/pathology ; Animals ; Class I Phosphatidylinositol 3-Kinases/physiology ; Collagen/metabolism ; Disease Models, Animal ; Disease Progression ; Epithelium/enzymology ; Male ; Mice, Mutant Strains ; Phosphorylation ; Prostate/enzymology ; Prostate/metabolism ; Prostate/pathology ; Prostatic Hyperplasia/enzymology ; Prostatic Hyperplasia/metabolism ; Prostatic Hyperplasia/pathology ; Prostatic Intraepithelial Neoplasia/enzymology ; Prostatic Intraepithelial Neoplasia/metabolism ; Prostatic Intraepithelial Neoplasia/pathology ; Prostatic Neoplasms/enzymology ; Prostatic Neoplasms/metabolism ; Prostatic Neoplasms/pathology ; Signal Transduction ; Smad2 Protein/metabolism ; Stromal Cells/metabolism ; Stromal Cells/pathology ; Transforming Growth Factor beta/physiology
    Chemical Substances Smad2 Protein ; Smad2 protein, mouse ; Transforming Growth Factor beta ; Collagen (9007-34-5) ; 1-phosphatidylinositol 3-kinase p110 subunit, mouse (EC 2.7.1.137) ; Class I Phosphatidylinositol 3-Kinases (EC 2.7.1.137)
    Language English
    Publishing date 2019-11-28
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 3119-7
    ISSN 1096-9896 ; 0022-3417
    ISSN (online) 1096-9896
    ISSN 0022-3417
    DOI 10.1002/path.5363
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