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Article ; Online: TAM Family Receptor Kinase Inhibition Reverses MDSC-Mediated Suppression and Augments Anti-PD-1 Therapy in Melanoma.

Holtzhausen, Alisha / Harris, William / Ubil, Eric / Hunter, Debra M / Zhao, Jichen / Zhang, Yuewei / Zhang, Dehui / Liu, Qingyang / Wang, Xiaodong / Graham, Douglas K / Frye, Stephen V / Earp, H Shelton

Cancer immunology research

2019 Volume 7, Issue 10, Page(s) 1672–1686

Abstract: Myeloid cell receptor tyrosine kinases TYRO3, AXL, and MERTK and their ligands, GAS6 and PROTEIN S, physiologically suppress innate immune responses, including in the tumor microenvironment. Here, we showed that myeloid-derived suppressor cells (MDSC) ... ...

Abstract	Myeloid cell receptor tyrosine kinases TYRO3, AXL, and MERTK and their ligands, GAS6 and PROTEIN S, physiologically suppress innate immune responses, including in the tumor microenvironment. Here, we showed that myeloid-derived suppressor cells (MDSC) dramatically upregulated TYRO3, AXL, and MERTK and their ligands [monocytic MDSCs (M-MDSC)>20-fold, polymorphonuclear MDSCs (PMN-MDSC)>15-fold] in tumor-bearing mice. MDSCs from tumor-bearing
MeSH term(s)	Adolescent ; Adult ; Aged ; Aged, 80 and over ; Animals ; Antineoplastic Agents, Immunological/pharmacology ; CD8-Positive T-Lymphocytes/immunology ; Cell Line, Tumor ; Female ; Healthy Volunteers ; Humans ; Male ; Melanoma/drug therapy ; Melanoma/metabolism ; Melanoma/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Middle Aged ; Myeloid-Derived Suppressor Cells/drug effects ; Myeloid-Derived Suppressor Cells/immunology ; Myeloid-Derived Suppressor Cells/metabolism ; Programmed Cell Death 1 Receptor/antagonists & inhibitors ; Proto-Oncogene Proteins/metabolism ; Receptor Protein-Tyrosine Kinases/metabolism ; Tumor Microenvironment ; Young Adult ; c-Mer Tyrosine Kinase/metabolism
Chemical Substances	Antineoplastic Agents, Immunological ; PDCD1 protein, human ; Programmed Cell Death 1 Receptor ; Proto-Oncogene Proteins ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1) ; TYRO3 protein, human (EC 2.7.10.1) ; axl receptor tyrosine kinase (EC 2.7.10.1) ; c-Mer Tyrosine Kinase (EC 2.7.10.1)
Language	English
Publishing date	2019-08-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2732489-8
ISSN	2326-6074 ; 2326-6066
ISSN (online)	2326-6074
ISSN	2326-6066
DOI	10.1158/2326-6066.CIR-19-0008
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Article ; Online: Epithelial cell-directed efferocytosis in the post-partum mammary gland is necessary for tissue homeostasis and future lactation

Earp H Shelton / Strunk Karen E / Hunter Debra M / Sandahl Melissa / Cook Rebecca S

BMC Developmental Biology, Vol 10, Iss 1, p

2010 Volume 122

Abstract: Abstract Background Mammary glands harbor a profound burden of apoptotic cells (ACs) during post-lactational involution, but little is known regarding mechanisms by which ACs are cleared from the mammary gland, or consequences if this process is ... ...

Abstract	Abstract Background Mammary glands harbor a profound burden of apoptotic cells (ACs) during post-lactational involution, but little is known regarding mechanisms by which ACs are cleared from the mammary gland, or consequences if this process is interrupted. We investigated AC clearance, also termed efferocytosis, during post-lactational remodeling, using mice deficient for MerTK, Axl, and Tyro3, three related receptor tyrosine kinases (RTKs) regulating macrophage-mediated efferocytosis in monocytes. MerTK expression, apoptosis and the accumulation of apoptotic debris were examined in histological sections of MerTK-deficient, Axl/Tyro3-deficient, and wild-type mammary glands harvested at specific time points during lactation and synchronized involution. The ability of primary mammary epithelial cells (MECs) to engulf ACs was assessed in culture. Transplant of MerTK-deficient mammary epithelium into cleared WT mammary fat pads was used to assess the contribution of WT mammary macrophages to post-lactational efferocytosis. Results ACs induced MerTK expression in MECs, resulting in elevated MerTK levels at the earliest stages of involution. Loss of MerTK resulted in AC accumulation in post-lactational MerTK-deficient mammary glands, but not in Axl and Tyro3-deficient mammary glands. Increased vascularization, fibrosis, and epithelial hyperproliferation were observed in MerTK-deficient mammary glands through at least 60 days post-weaning, due to failed efferocytosis after lactation, but did not manifest in nulliparous mice. WT host-derived macrophages failed to rescue efferocytosis in transplanted MerTK-deficient mammary epithelium. Conclusion Efferocytosis by MECs through MerTK is crucial for mammary gland homeostasis and function during the post-lactational period. Efferocytosis by MECs thus limits pathologic consequences associated with the apoptotic load following lactation.
Keywords	Biology (General) ; QH301-705.5
Subject code	630
Language	English
Publishing date	2010-12-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
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Article ; Online: Epithelial cell-directed efferocytosis in the post-partum mammary gland is necessary for tissue homeostasis and future lactation.

Sandahl, Melissa / Hunter, Debra M / Strunk, Karen E / Earp, H Shelton / Cook, Rebecca S

BMC developmental biology

2010 Volume 10, Page(s) 122

Abstract: Background: Mammary glands harbor a profound burden of apoptotic cells (ACs) during post-lactational involution, but little is known regarding mechanisms by which ACs are cleared from the mammary gland, or consequences if this process is interrupted. We ...

Abstract	Background: Mammary glands harbor a profound burden of apoptotic cells (ACs) during post-lactational involution, but little is known regarding mechanisms by which ACs are cleared from the mammary gland, or consequences if this process is interrupted. We investigated AC clearance, also termed efferocytosis, during post-lactational remodeling, using mice deficient for MerTK, Axl, and Tyro3, three related receptor tyrosine kinases (RTKs) regulating macrophage-mediated efferocytosis in monocytes. MerTK expression, apoptosis and the accumulation of apoptotic debris were examined in histological sections of MerTK-deficient, Axl/Tyro3-deficient, and wild-type mammary glands harvested at specific time points during lactation and synchronized involution. The ability of primary mammary epithelial cells (MECs) to engulf ACs was assessed in culture. Transplant of MerTK-deficient mammary epithelium into cleared WT mammary fat pads was used to assess the contribution of WT mammary macrophages to post-lactational efferocytosis. Results: ACs induced MerTK expression in MECs, resulting in elevated MerTK levels at the earliest stages of involution. Loss of MerTK resulted in AC accumulation in post-lactational MerTK-deficient mammary glands, but not in Axl and Tyro3-deficient mammary glands. Increased vascularization, fibrosis, and epithelial hyperproliferation were observed in MerTK-deficient mammary glands through at least 60 days post-weaning, due to failed efferocytosis after lactation, but did not manifest in nulliparous mice. WT host-derived macrophages failed to rescue efferocytosis in transplanted MerTK-deficient mammary epithelium. Conclusion: Efferocytosis by MECs through MerTK is crucial for mammary gland homeostasis and function during the post-lactational period. Efferocytosis by MECs thus limits pathologic consequences associated with the apoptotic load following lactation.
MeSH term(s)	Animals ; Apoptosis ; Epithelial Cells/metabolism ; Female ; Homeostasis ; Lactation ; Macrophages ; Mammary Glands, Animal/cytology ; Mammary Glands, Animal/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Phagocytosis ; Polymerase Chain Reaction ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins/metabolism ; Receptor Protein-Tyrosine Kinases/genetics ; Receptor Protein-Tyrosine Kinases/metabolism ; c-Mer Tyrosine Kinase
Chemical Substances	Proto-Oncogene Proteins ; MERTK protein, human (EC 2.7.10.1) ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1) ; TYRO3 protein, human (EC 2.7.10.1) ; axl receptor tyrosine kinase (EC 2.7.10.1) ; c-Mer Tyrosine Kinase (EC 2.7.10.1)
Language	English
Publishing date	2010-12-30
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1471-213X
ISSN (online)	1471-213X
DOI	10.1186/1471-213X-10-122
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Article ; Online: SGC-GAK-1: A Chemical Probe for Cyclin G Associated Kinase (GAK).

Asquith, Christopher R M / Berger, Benedict-Tilman / Wan, Jing / Bennett, James M / Capuzzi, Stephen J / Crona, Daniel J / Drewry, David H / East, Michael P / Elkins, Jonathan M / Fedorov, Oleg / Godoi, Paulo H / Hunter, Debra M / Knapp, Stefan / Müller, Susanne / Torrice, Chad D / Wells, Carrow I / Earp, H Shelton / Willson, Timothy M / Zuercher, William J

Journal of medicinal chemistry

2019 Volume 62, Issue 5, Page(s) 2830–2836

Abstract: We describe SGC-GAK-1 (11), a potent, selective, and cell-active inhibitor of cyclin G-associated kinase (GAK), together with a structurally related negative control SGC-GAK-1N (14). 11 was highly selective in an in vitro kinome-wide screen, but cellular ...

Abstract	We describe SGC-GAK-1 (11), a potent, selective, and cell-active inhibitor of cyclin G-associated kinase (GAK), together with a structurally related negative control SGC-GAK-1N (14). 11 was highly selective in an in vitro kinome-wide screen, but cellular engagement assays defined RIPK2 as a collateral target. We identified 18 as a potent RIPK2 inhibitor lacking GAK activity. Together, this chemical probe set can be used to interrogate GAK cellular biology.
MeSH term(s)	Cyclin G/metabolism ; HEK293 Cells ; Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; Male ; Molecular Probes/metabolism ; Protein-Serine-Threonine Kinases/metabolism
Chemical Substances	Cyclin G ; Intracellular Signaling Peptides and Proteins ; Molecular Probes ; GAK protein, human (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2019-02-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.8b01213
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Article ; Online: MerTK inhibition in tumor leukocytes decreases tumor growth and metastasis.

Cook, Rebecca S / Jacobsen, Kristen M / Wofford, Anne M / DeRyckere, Deborah / Stanford, Jamie / Prieto, Anne L / Redente, Elizabeth / Sandahl, Melissa / Hunter, Debra M / Strunk, Karen E / Graham, Douglas K / Earp, H Shelton

The Journal of clinical investigation

2013 Volume 123, Issue 8, Page(s) 3231–3242

Abstract: MerTK, a receptor tyrosine kinase (RTK) of the TYRO3/AXL/MerTK family, is expressed in myeloid lineage cells in which it acts to suppress proinflammatory cytokines following ingestion of apoptotic material. Using syngeneic mouse models of breast cancer, ... ...

Abstract	MerTK, a receptor tyrosine kinase (RTK) of the TYRO3/AXL/MerTK family, is expressed in myeloid lineage cells in which it acts to suppress proinflammatory cytokines following ingestion of apoptotic material. Using syngeneic mouse models of breast cancer, melanoma, and colon cancer, we found that tumors grew slowly and were poorly metastatic in MerTK-/- mice. Transplantation of MerTK-/- bone marrow, but not wild-type bone marrow, into lethally irradiated MMTV-PyVmT mice (a model of metastatic breast cancer) decreased tumor growth and altered cytokine production by tumor CD11b+ cells. Although MerTK expression was not required for tumor infiltration by leukocytes, MerTK-/- leukocytes exhibited lower tumor cell-induced expression of wound healing cytokines, e.g., IL-10 and growth arrest-specific 6 (GAS6), and enhanced expression of acute inflammatory cytokines, e.g., IL-12 and IL-6. Intratumoral CD8+ T lymphocyte numbers were higher and lymphocyte proliferation was increased in tumor-bearing MerTK-/- mice compared with tumor-bearing wild-type mice. Antibody-mediated CD8+ T lymphocyte depletion restored tumor growth in MerTK-/- mice. These data demonstrate that MerTK signaling in tumor-associated CD11b+ leukocytes promotes tumor growth by dampening acute inflammatory cytokines while inducing wound healing cytokines. These results suggest that inhibition of MerTK in the tumor microenvironment may have clinical benefit, stimulating antitumor immune responses or enhancing immunotherapeutic strategies.
MeSH term(s)	Animals ; CD8-Positive T-Lymphocytes/enzymology ; Colonic Neoplasms/enzymology ; Colonic Neoplasms/immunology ; Colonic Neoplasms/pathology ; Cytokines/genetics ; Cytokines/metabolism ; Disease Resistance/immunology ; Female ; Gene Expression Regulation, Neoplastic ; Leukocytes/enzymology ; Male ; Mammary Neoplasms, Experimental/enzymology ; Mammary Neoplasms, Experimental/immunology ; Mammary Neoplasms, Experimental/pathology ; Melanoma, Experimental/enzymology ; Melanoma, Experimental/immunology ; Melanoma, Experimental/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neoplasm Transplantation ; Proto-Oncogene Proteins ; Receptor Protein-Tyrosine Kinases ; Transcriptome ; Tumor Burden ; Tumor Microenvironment ; c-Mer Tyrosine Kinase
Chemical Substances	Cytokines ; Proto-Oncogene Proteins ; Mertk protein, mouse (EC 2.7.10.1) ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1) ; c-Mer Tyrosine Kinase (EC 2.7.10.1)
Language	English
Publishing date	2013-07-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI67655
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Article: HER4 D-box sequences regulate mitotic progression and degradation of the nuclear HER4 cleavage product s80HER4.

Strunk, Karen E / Husted, Carty / Miraglia, Leah C / Sandahl, Melissa / Rearick, William A / Hunter, Debra M / Earp, H Shelton / Muraoka-Cook, Rebecca S

Cancer research

2007 Volume 67, Issue 14, Page(s) 6582–6590

Abstract: Heregulin-mediated activation of HER4 initiates receptor cleavage (releasing an 80-kDa HER4 intracellular domain, s80(HER4), containing nuclear localization sequences) and results in G(2)-M delay by unknown signaling mechanisms. We report herein that s80( ...

Abstract	Heregulin-mediated activation of HER4 initiates receptor cleavage (releasing an 80-kDa HER4 intracellular domain, s80(HER4), containing nuclear localization sequences) and results in G(2)-M delay by unknown signaling mechanisms. We report herein that s80(HER4) contains a functional cyclin B-like sequence known as a D-box, which targets proteins for degradation by anaphase-promoting complex (APC)/cyclosome, a multisubunit ubiquitin ligase. s80(HER4) ubiquitination and proteasomal degradation occurred during mitosis but not during S phase. Inhibition of an APC subunit (APC2) using short interfering RNA knockdown impaired s80(HER4) degradation. Mutation of the s80(HER4) D-box sequence stabilized s80(HER4) during mitosis, and s80(HER4)-dependent growth inhibition via G(2)-M delay was significantly greater with the D-box mutant. Polyomavirus middle T antigen-transformed HC11 cells expressing s80(HER4) resulted in smaller, less proliferative, more differentiated tumors in vivo than those expressing kinase-dead s80(HER4) or the empty vector. Cells expressing s80(HER4) with a disrupted D-box did not form tumors, instead forming differentiated ductal structures. These results suggest that cell cycle-dependent degradation of s80(HER4) limits its growth-inhibitory action, and stabilization of s80(HER4) enhances tumor suppression, thus providing a link between HER4-mediated growth inhibition and cell cycle control.
MeSH term(s)	Amino Acid Motifs ; Antigens, Polyomavirus Transforming/metabolism ; Cell Division ; Cell Line, Transformed ; Cell Line, Tumor ; Cell Nucleus/metabolism ; G2 Phase ; Green Fluorescent Proteins/metabolism ; HeLa Cells ; Humans ; Mitosis ; Neuregulin-1/metabolism ; Protein Structure, Tertiary ; Receptor, Epidermal Growth Factor/physiology ; Receptor, ErbB-4 ; Ubiquitin/metabolism
Chemical Substances	Antigens, Polyomavirus Transforming ; Neuregulin-1 ; Ubiquitin ; Green Fluorescent Proteins (147336-22-9) ; ERBB4 protein, human (EC 2.7.10.1) ; Receptor, Epidermal Growth Factor (EC 2.7.10.1) ; Receptor, ErbB-4 (EC 2.7.10.1)
Language	English
Publishing date	2007-07-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-06-4145
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Article ; Online: ErbB4 splice variants Cyt1 and Cyt2 differ by 16 amino acids and exert opposing effects on the mammary epithelium in vivo.

Muraoka-Cook, Rebecca S / Sandahl, Melissa A / Strunk, Karen E / Miraglia, Leah C / Husted, Carty / Hunter, Debra M / Elenius, Klaus / Chodosh, Lewis A / Earp, H Shelton

Molecular and cellular biology

2009 Volume 29, Issue 18, Page(s) 4935–4948

Abstract: Data concerning the prognostic value of ErbB4 in breast cancer and effects on cell growth have varied in published reports, perhaps due to the unknown signaling consequences of expression of the intracellular proteolytic ErbB4 s80(HER4) fragment or due ... ...

Abstract	Data concerning the prognostic value of ErbB4 in breast cancer and effects on cell growth have varied in published reports, perhaps due to the unknown signaling consequences of expression of the intracellular proteolytic ErbB4 s80(HER4) fragment or due to differing signaling capabilities of alternatively spliced ErbB4 isoforms. One isoform (Cyt1) contains a 16-residue intracellular sequence that is absent from the other (Cyt2). We expressed s80(Cyt1) and s80(Cyt2) in HC11 mammary epithelial cells, finding diametrically opposed effects on the growth and organization of colonies in three-dimensional matrices. Whereas expression of s80(Cyt1) decreased growth and increased the rate of three-dimensional lumen formation, that of s80(Cyt2) increased proliferation without promoting lumen formation. These results were recapitulated in vivo, using doxycycline-inducible, mouse breast-transgenic expression of s80(Cyt1) amd s80(Cyt2). Expression of s80(Cyt1) decreased growth of the mammary ductal epithelium, caused precocious STAT5a activation and lactogenic differentiation, and increased cell surface E-cadherin levels. Remarkably, ductal growth inhibition by s80(Cyt1) occurred simultaneously with lobuloalveolar growth that was unimpeded by s80(Cyt1), suggesting that the response to ErbB4 may be influenced by the epithelial subtype. In contrast, expression of s80(Cyt2) caused epithelial hyperplasia, increased Wnt and nuclear beta-catenin expression, and elevated expression of c-myc and cyclin D1 in the mammary epithelium. These results demonstrate that the Cyt1 and Cyt2 ErbB4 isoforms, differing by only 16 amino acids, exhibit markedly opposing effects on mammary epithelium growth and differentiation.
MeSH term(s)	Alternative Splicing/genetics ; Amino Acid Motifs ; Amino Acids/metabolism ; Animals ; Cell Line ; Cell Nucleus/metabolism ; Cell Proliferation ; Epithelium/metabolism ; ErbB Receptors/chemistry ; ErbB Receptors/metabolism ; Female ; Gene Expression Regulation ; Humans ; Mammary Glands, Animal/cytology ; Mammary Glands, Animal/metabolism ; Mice ; Milk Proteins/genetics ; Milk Proteins/metabolism ; Phosphorylation ; Pregnancy ; Protein Isoforms/chemistry ; Protein Isoforms/metabolism ; Protein Structure, Tertiary ; Puberty/metabolism ; Receptor, ErbB-4 ; STAT5 Transcription Factor/metabolism ; Signal Transduction ; beta Catenin/metabolism
Chemical Substances	Amino Acids ; Milk Proteins ; Protein Isoforms ; STAT5 Transcription Factor ; Stat5a protein, mouse ; beta Catenin ; ERBB4 protein, human (EC 2.7.10.1) ; ErbB Receptors (EC 2.7.10.1) ; Erbb4 protein, mouse (EC 2.7.10.1) ; Receptor, ErbB-4 (EC 2.7.10.1)
Language	English
Publishing date	2009-07-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	779397-2
ISSN	1098-5549 ; 0270-7306
ISSN (online)	1098-5549
ISSN	0270-7306
DOI	10.1128/MCB.01705-08
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Article ; Online: UNC569, a novel small-molecule mer inhibitor with efficacy against acute lymphoblastic leukemia in vitro and in vivo.

Molecular cancer therapeutics

2013 Volume 12, Issue 11, Page(s) 2367–2377

Abstract: Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Although survival rates have improved, patients with certain biologic subtypes still have suboptimal outcomes. Current chemotherapeutic regimens are associated with short- and ... ...

Abstract	Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Although survival rates have improved, patients with certain biologic subtypes still have suboptimal outcomes. Current chemotherapeutic regimens are associated with short- and long-term toxicities and novel, less toxic therapeutic strategies are needed. Mer receptor tyrosine kinase is ectopically expressed in ALL patient samples and cell lines. Inhibition of Mer expression reduces prosurvival signaling, increases chemosensitivity, and delays development of leukemia in vivo, suggesting that Mer tyrosine kinase inhibitors are excellent candidates for targeted therapies. Brain and spinal tumors are the second most common malignancies in childhood. Multiple chemotherapy approaches and radiotherapies have been attempted, yet overall survival remains dismal. Mer is also abnormally expressed in atypical teratoid/rhabdoid tumors (AT/RT), providing a rationale for targeting Mer as a therapeutic strategy. We have previously described UNC569, the first small-molecule Mer inhibitor. This article describes the biochemical and biologic effects of UNC569 in ALL and AT/RT. UNC569 inhibited Mer activation and downstream signaling through ERK1/2 and AKT, determined by Western blot analysis. Treatment with UNC569 reduced proliferation/survival in liquid culture, decreased colony formation in methylcellulose/soft agar, and increased sensitivity to cytotoxic chemotherapies. MYC transgenic zebrafish with T-ALL were treated with UNC569 (4 μmol/L for two weeks). Fluorescence was quantified as indicator of the distribution of lymphoblasts, which express Mer and enhanced GFP. UNC569 induced more than 50% reduction in tumor burden compared with vehicle- and mock-treated fish. These data support further development of Mer inhibitors as effective therapies in ALL and AT/RT.
MeSH term(s)	Animals ; Animals, Genetically Modified ; Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Gene Expression Regulation, Leukemic/drug effects ; Humans ; Jurkat Cells ; MAP Kinase Signaling System/drug effects ; Molecular Targeted Therapy ; Neoplasms, Experimental ; Phosphorylation/drug effects ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology ; Proto-Oncogene Proteins/antagonists & inhibitors ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-akt/genetics ; Proto-Oncogene Proteins c-akt/metabolism ; Pyrazoles/pharmacology ; Pyrimidines/pharmacology ; Receptor Protein-Tyrosine Kinases/antagonists & inhibitors ; Receptor Protein-Tyrosine Kinases/metabolism ; Rhabdoid Tumor/drug therapy ; Rhabdoid Tumor/metabolism ; Rhabdoid Tumor/pathology ; Teratoma/drug therapy ; Teratoma/metabolism ; Teratoma/pathology ; Zebrafish ; c-Mer Tyrosine Kinase
Chemical Substances	Antineoplastic Agents ; Proto-Oncogene Proteins ; Pyrazoles ; Pyrimidines ; UNC569 ; MERTK protein, human (EC 2.7.10.1) ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1) ; c-Mer Tyrosine Kinase (EC 2.7.10.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
Language	English
Publishing date	2013-08-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2063563-1
ISSN	1538-8514 ; 1535-7163
ISSN (online)	1538-8514
ISSN	1535-7163
DOI	10.1158/1535-7163.MCT-13-0040
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Article: Heregulin-dependent delay in mitotic progression requires HER4 and BRCA1.

Muraoka-Cook, Rebecca S / Caskey, Laura S / Sandahl, Melissa A / Hunter, Debra M / Husted, Carty / Strunk, Karen E / Sartor, Carolyn I / Rearick, William A / McCall, Wesley / Sgagias, Magdalene K / Cowan, Kenneth H / Earp, H Shelton

Molecular and cellular biology

2006 Volume 26, Issue 17, Page(s) 6412–6424

Abstract: HER4 expression in human breast cancers correlates with a positive prognosis. While heregulin inhibits the growth of HER4-positive breast cancer cells, it does so by undefined mechanisms. We demonstrate that heregulin-induced HER4 activity inhibits cell ... ...

Abstract	HER4 expression in human breast cancers correlates with a positive prognosis. While heregulin inhibits the growth of HER4-positive breast cancer cells, it does so by undefined mechanisms. We demonstrate that heregulin-induced HER4 activity inhibits cell proliferation and delays G(2)/M progression of breast cancer cells. While investigating pathways of G(2)/M delay, we noted that heregulin increased the expression of BRCA1 in a HER4-dependent, HER2-independent manner. Induction of BRCA1 by HER4 occurred independently of the cell cycle. Moreover, BRCA1 expression was elevated in HER4-postive human breast cancer specimens. Heregulin stimulated c-Jun N-terminal kinase (JNK), and pharmacologic inhibition of JNK impaired heregulin-enhanced expression of BRCA1 and mitotic delay; inhibition of Erk1/2 did not. Knockdown of BRCA1 with small interfering RNA in a human breast cancer cell line interfered with HER4-mediated mitotic delay. Heregulin/HER4-dependent mitotic delay was examined further with an isogenic pair of mouse mammary epithelial cells (MECs) derived from mice harboring homozygous LoxP sites flanking exon 11 of BRCA1, such that one cell line expressed BRCA1 while the other cell line, after Cre-mediated excision, did not. BRCA1-positive MECs displayed heregulin-dependent mitotic delay; however, the isogenic BRCA1-negative MECs did not. These results suggest that heregulin-mediated growth inhibition in HER4-postive breast cancer cells requires BRCA1.
MeSH term(s)	Animals ; BRCA1 Protein/deficiency ; BRCA1 Protein/genetics ; BRCA1 Protein/metabolism ; Breast Neoplasms/pathology ; Epithelial Cells/cytology ; Epithelial Cells/drug effects ; ErbB Receptors/genetics ; ErbB Receptors/metabolism ; Exons/genetics ; G2 Phase/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; HeLa Cells ; Humans ; Mammary Glands, Animal/cytology ; Mice ; Mitogen-Activated Protein Kinase 8/metabolism ; Mitogen-Activated Protein Kinase 9/metabolism ; Mitosis/drug effects ; Neuregulin-1/pharmacology ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Receptor, ErbB-2/metabolism ; Receptor, ErbB-4 ; Tumor Cells, Cultured
Chemical Substances	BRCA1 Protein ; Neuregulin-1 ; RNA, Messenger ; Mitogen-Activated Protein Kinase 9 (EC 2.7.1.24) ; ERBB4 protein, human (EC 2.7.10.1) ; ErbB Receptors (EC 2.7.10.1) ; Erbb4 protein, mouse (EC 2.7.10.1) ; Receptor, ErbB-2 (EC 2.7.10.1) ; Receptor, ErbB-4 (EC 2.7.10.1) ; Mitogen-Activated Protein Kinase 8 (EC 2.7.11.24)
Language	English
Publishing date	2006-08-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	779397-2
ISSN	1098-5549 ; 0270-7306
ISSN (online)	1098-5549
ISSN	0270-7306
DOI	10.1128/MCB.01950-05
Database	MEDical Literature Analysis and Retrieval System OnLINE

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