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[Neratinib + Valproate] exposure permanently reduces ERBB1 and RAS expression in 4T1 mammary tumors and enhances M1 macrophage infiltration.

ABSTRACT: The irreversible ERBB1/2/4 inhibitor neratinib has been shown in vitro to rapidly reduce the expression of ERBB1/2/4 and RAS proteins via autophagic/lysosomal degradation. We have recently demonstrated that neratinib and valproate interact to suppress the growth of 4T1 mammary tumors but had not defined whether the [neratinib + valproate] drug combination, in a mouse, had altered the biology of the 4T1 cells. Exposure of 4T1 mammary tumors to [neratinib + valproate] for three days resulted, two weeks later, in tumors that expressed less ERBB1, K-RAS, N-RAS, indoleamine-pyrrole 2,3-dioxygenase (IDO-1), ornithine decarboxylase (ODC) and had increased Class I MHCA expression. Tumors previously exposed to [neratinib + valproate] grew more slowly than those exposed to vehicle control and contained more CD8+ cells and activated NK cells. M1 but not M2 macrophage infiltration was significantly enhanced by the drug combination. In vitro exposure of 4T1 tumor cells to [neratinib + valproate] variably reduced the expression of histone deacetylases 1-11. In vivo, prior exposure of tumors to [neratinib + valproate] permanently reduced the expression of HDACs 1-3, 6 and 10. Combined knock down of HDACs 1/2/3 or of 3/10 rapidly reduced the expression IDO-1, and ODC and increased the expression of MHCA. H&E staining of normal tissues at animal nadir revealed no obvious cyto-architectural differences between control and drug-treated animals. We conclude that [neratinib + valproate] evolves 4T1 tumors to grow more slowly and to be more sensitive to checkpoint immunotherapy antibodies.

SUBMITTER: Booth L

PROVIDER: S-EPMC5814195 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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[Neratinib + Valproate] exposure permanently reduces ERBB1 and RAS expression in 4T1 mammary tumors and enhances M1 macrophage infiltration.

Booth Laurence L Roberts Jane L JL Rais Rumeesa R Kirkwood John J Avogadri-Connors Francesca F Cutler Richard E RE Lalani Alshad S AS Poklepovic Andrew A Dent Paul P

Oncotarget 20171226 5

The irreversible ERBB1/2/4 inhibitor neratinib has been shown <i>in vitro</i> to rapidly reduce the expression of ERBB1/2/4 and RAS proteins via autophagic/lysosomal degradation. We have recently demonstrated that neratinib and valproate interact to suppress the growth of 4T1 mammary tumors but had not defined whether the [neratinib + valproate] drug combination, in a mouse, had altered the biology of the 4T1 cells. Exposure of 4T1 mammary tumors to [neratinib + valproate] for three days resulte ...[more]

PMID: 29464055

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Project description:BACKGROUND:Peripheral nerve injury causes limb muscle/bone atrophy, leading to chronic pain. However, the mechanisms underlying muscle/bone atrophy after peripheral nerve injury remain unknown. It was recently reported that M1 macrophages are the main factors responsible for neurogenic inflammation after peripheral nerve injury. We hypothesized that M1 macrophages are important in muscle/bone atrophy after nerve injury. Therefore, we investigated the influence of M1 macrophages on muscle/bone atrophy after nerve injury in mice to prevent muscle/bone atrophy by suppressing M1 macrophages. METHODS:Hindlimb muscle weight and total bone density were measured in a chronic constriction injury (CCI) mouse model. Immunohistochemical analysis and intravital microscopy were performed to visualize hindlimb muscles/bones, and cells were quantified using flow cytometry. We compared M1 macrophage infiltration into muscles/bones and muscle/bone atrophy between macrophage depletion and untreated groups. We also investigated muscle/bone atrophy using administration models for anti-inflammatory and neuropathic pain drugs. RESULTS:Peripheral nerve injury caused significant reduction in muscle weight and total bone density at 1 and 3 weeks after CCI, respectively, compared with that in controls. Osteoclast numbers were significantly higher at 1 week after CCI in the CCI group than in the control group. M1 macrophage infiltration into muscles was observed from 2 h after CCI via intravital microscopy and 1 week after CCI, and it was significantly higher 1 week after CCI than in the control group. In the macrophage depletion group, dexamethasone, pregabalin, and loxoprofen groups, M1 macrophage infiltration into muscles/bones was significantly lower and muscle weight and total bone density were significantly higher than in the untreated group. CONCLUSIONS:M1 macrophage infiltration exacerbates muscle/bone atrophy after peripheral nerve injury. By suppressing M1 macrophages at the neural injury local site, muscle/bone atrophy could be avoided.

Project description:BackgroundThe four ERBB tyrosine kinase family members [ERBB1 (epidermal growth factor receptor, EGFR), ERBB2 (HER2), ERBB3 (HER3), and ERBB4 (HER4)] (ERBB receptor family) have been shown, according to previous studies, to be related to the cutaneous melanoma. ERBB3 is the only member of the ERBBs that lacks tyrosine kinase activity and thus needs to dimer with other tyrosine kinases receptors to trigger the signaling pathway, while ERBB3 may dimer with all members of the ERBB family. Melanoma progression depends on activation of ERBB signaling, especially the ERBB3/ERBB2 cascade. There are lymphocytes and T cell infiltrates in melanoma. Numerous pieces of evidences indicate that local immune status plays an important role in the formation of anti-tumor immune responses. However, the relationship between the ERBBs and prognosis and immune infiltration in cutaneous melanoma is not completely clear.MethodsThe expression of the ERBBs was analyzed through the Oncomine database, Gene Expression Profiling Interactive Analysis (GEPIA), respectively. Immunohistochemistry of ERBBs was obtained from the Human Protein Atlas is increased before HPA database. ERBBs genes expression and mutation analysis in cutaneous melanoma from the cBioPortal. Functional annotation and Kyoto Encyclopedia of Genes and Genomes is increased before KEGG pathway enrichment analysis from the Metascape. Correlations between ERBBs and 31 genes that were close to each other and frequently altered were explored by GEPIA. Using the GEPIA database, we also investigated the relationship between ERBBs and myeloid-derived suppressor cells (MDSC) in cutaneous melanoma. The disease-free survival and different tumor stages of ERBBs were evaluated by GEPIA. The correlation of ERBBs and tumor-infiltrating immune cells and prognostic(5 years survival rates) was tested by the Tumor Immune Estimation Resource (TIMER).ResultsIn general, the expression levels of ERBB1/2 in cutaneous melanoma were lower than those in normal skin tissue. By contrast, the ERBB3 expression level was higher in cutaneous melanoma than in normal skin tissue. Low expression of ERBB1/2 and high expression of ERBB3 were detrimental to the 5 years survival of cutaneous melanoma patients (ERBB1: log-rank P: 0.03; ERBB2: log-rank P: 0.008; ERBB3: log-rank P: 0.039). ERBB4 expression may not affect the prognosis of patients with cutaneous melanoma. ERBBs may not play a role in the tumor stage and disease-free survival in cutaneous melanoma patients. The relationship between the ERBB family and 31 genes that were close to each other and frequently altered is demonstrated as the genes regulated by the ERBB family being mainly concentrated in the RAS/RAF/MEK/ERK signaling pathway. ERBB2 can induce infiltration of CD8+ T cells and B cells, while ERBB3 can induce infiltration of CD4+ T cells, CD8+ T cells, and Neutrophil cells. ERBBs are more significantly associated with M1 macrophages, dendritic cells, Th1, Th2, Th17, and Treg cellular immune markers (Cor > 0.2). ERBB2/3 were related to MDSC in cutaneous melanoma, including human mononuclear myeloid-derived suppressor cells (M-MDSC) and polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC), and may influence the progression of cutaneous melanoma through MDSC, but the conclusion needs further probing.ConclusionThis study investigated the prognosis and immune infiltration of the ERBB family in cutaneous melanoma. Our results suggest that ERBB1/2/3 may serve as early prognostic markers and potential therapeutic targets in cutaneous melanoma.

Dataset Information

[Neratinib + Valproate] exposure permanently reduces ERBB1 and RAS expression in 4T1 mammary tumors and enhances M1 macrophage infiltration.

Publications

[Neratinib + Valproate] exposure permanently reduces ERBB1 and RAS expression in 4T1 mammary tumors and enhances M1 macrophage infiltration.

Similar Datasets

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