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

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

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
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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
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Article ; Online: The Report of the 2022-2023 AACP Research and Graduate Affairs Committee.

Swanson, Steven M / Birnbaum, Angela / Brackett, Christopher / Lipscomb, Justina / Moniri, Nader H / Swaan, Peter W / Lei, Wei / Farrell, Dorothy

American journal of pharmaceutical education

2023 Volume 87, Issue 8, Page(s) 100556

MeSH term(s)	Humans ; Education, Pharmacy ; Education, Pharmacy, Graduate ; Curriculum
Language	English
Publishing date	2023-07-11
Publishing country	United States
Document type	Practice Guideline
ZDB-ID	603807-4
ISSN	1553-6467 ; 0002-9459
ISSN (online)	1553-6467
ISSN	0002-9459
DOI	10.1016/j.ajpe.2023.100556
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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
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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
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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
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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
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Article ; Online: Special Issue in Honor of Professor Susan Band Horwitz.

Mooberry, Susan L / Kingston, David G I / Smith, Amos B / Swanson, Steven M / Wani, Mansukh C

Journal of natural products

2018 Volume 81, Issue 3, Page(s) 449–450

MeSH term(s)	Humans ; Medical Laboratory Personnel ; Neoplasms/drug therapy ; Pharmaceutical Preparations/chemistry ; Pharmacology/methods
Chemical Substances	Pharmaceutical Preparations
Language	English
Publishing date	2018-04-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	304325-3
ISSN	1520-6025 ; 0163-3864
ISSN (online)	1520-6025
ISSN	0163-3864
DOI	10.1021/acs.jnatprod.8b00098
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Article ; Online: Potential Anticancer Agents Characterized from Selected Tropical Plants.

Ren, Yulin / de Blanco, Esperanza J Carcache / Fuchs, James R / Soejarto, Djaja D / Burdette, Joanna E / Swanson, Steven M / Kinghorn, A Douglas

Journal of natural products

2019 Volume 82, Issue 3, Page(s) 657–679

Abstract: Higher plants are well known for their value in affording clinically useful anticancer agents, with such compounds acting against cancer cells by a range of mechanisms of action. There remains a strong interest in the discovery and development of plant ... ...

Abstract	Higher plants are well known for their value in affording clinically useful anticancer agents, with such compounds acting against cancer cells by a range of mechanisms of action. There remains a strong interest in the discovery and development of plant secondary metabolites as additional cancer chemotherapeutic lead compounds. In the present review, progress on the discovery of plant-derived compounds of the biflavonoid, lignan, sesquiterpene, steroid, and xanthone structural types is presented. Several potential anticancer leads of these types have been characterized from tropical plants collected in three countries as part of our ongoing collaborative multi-institutional project. Preliminary structure-activity relationships and work on in vivo testing and cellular mechanisms of action are also discussed. In addition, the relevant work reported by other groups on the same compound classes is included herein.
MeSH term(s)	Antineoplastic Agents, Phytogenic/chemistry ; Antineoplastic Agents, Phytogenic/isolation & purification ; Antineoplastic Agents, Phytogenic/pharmacology ; Molecular Structure ; Plants/chemistry ; Structure-Activity Relationship ; Tropical Climate
Chemical Substances	Antineoplastic Agents, Phytogenic
Language	English
Publishing date	2019-03-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	304325-3
ISSN	1520-6025 ; 0163-3864
ISSN (online)	1520-6025
ISSN	0163-3864
DOI	10.1021/acs.jnatprod.9b00018
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Article ; Online: The role of WNT10B in normal prostate gland development and prostate cancer.

Madueke, Ikenna / Hu, Wen-Yang / Hu, Danping / Swanson, Steven M / Vander Griend, Donald / Abern, Michael / Prins, Gail S

The Prostate

2019 Volume 79, Issue 14, Page(s) 1692–1704

Abstract: Background: WNT signaling is implicated in embryonic development, and in adult tissue homeostasis, while its deregulation is evident in disease. This study investigates the unique roles of canonical WNT10B in both normal prostate development and ... ...

Abstract	Background: WNT signaling is implicated in embryonic development, and in adult tissue homeostasis, while its deregulation is evident in disease. This study investigates the unique roles of canonical WNT10B in both normal prostate development and prostate cancer (PCa) progression. Methods: Organ culture and rat ventral prostates (VPs) were used to study Wnt10b ontogeny and growth effect of WNT10B protein. PB-SV40 LTag rat VPs were utilized for Wnt expression polymerase chain reaction (PCR) array and immunohistochemistry. Human localized PCa tissue microarrays (TMAs) were investigated for differential WNT10B expression. Human RNA-seq data sets were queried for differential expression of WNT10B in metastatic and localized PCa. Knockdown of WNT10B in PC3 cells was utilized to study its effects on proliferation, stemness, epithelial to mesenchymal transition (EMT), and xenograft propagation. Results: Wnt10b expression was highest at birth and rapidly declined in the postnatal rat VP. Exogenous WNT10B addition to culture developing VPs decreased growth suggesting an antiproliferative role. VPs from PB-SV40 LTag rats with localized PCa showed a 25-fold reduction in Wnt10b messenger RNA (mRNA) expession, confirmed at the protein level. Human PCa TMAs revealed elevated WNT10B protein in prostate intraepithelial neoplasia compared with normal prostates but reduced levels in localized PCa specimens. In contrast, RNA-seq data set of annotated human PCa metastasis found a significant increase in WNT10B mRNA expression compared with localized tumors suggesting stage-specific functions of WNT10B. Similarly, WNT10B mRNA levels were increased in metastatic cell lines PC3, PC3M, as well as in HuSLC, a PCa stem-like cell line, as compared with disease-free primary prostate epithelial cells. WNT10B knockdown in PC3 cells reduced expression of EMT genes, MMP9 and stemness genes NANOG and SOX2 and markedly reduced the stem cell-like side population. Furthermore, loss of WNT10B abrogated the ability of PC3 cells to propagate tumors via serial transplantation. Conclusions: Taken together, these results suggest a dual role for WNT10B in normal development and in PCa progression with opposing functions depending on disease stage. We propose that decreased WNT10B levels in localized cancer allow for a hyperproliferative state, whereas increased levels in advanced disease confer a stemness and malignant propensity which is mitigated by knocking down WNT10B levels. This raises the potential for WNT10B as a novel target for therapeutic intervention in metastatic PCa.
MeSH term(s)	Animals ; Cell Line, Tumor ; Cell Proliferation ; Down-Regulation ; Epithelial-Mesenchymal Transition ; Gene Expression ; Gene Knockdown Techniques ; Humans ; Male ; Mice ; Mice, Nude ; Neoplasm Metastasis/pathology ; Neoplasm Transplantation ; Organ Culture Techniques ; PC-3 Cells ; Prostate/growth & development ; Prostatic Intraepithelial Neoplasia/pathology ; Prostatic Neoplasms/pathology ; Proto-Oncogene Proteins/analysis ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins/physiology ; RNA, Messenger/analysis ; Rats ; Rats, Sprague-Dawley ; Wnt Proteins/analysis ; Wnt Proteins/genetics ; Wnt Proteins/physiology
Chemical Substances	Proto-Oncogene Proteins ; RNA, Messenger ; WNT10B protein, human ; Wnt Proteins
Language	English
Publishing date	2019-08-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	604707-5
ISSN	1097-0045 ; 0270-4137
ISSN (online)	1097-0045
ISSN	0270-4137
DOI	10.1002/pros.23894
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