Overexpression of the receptor tyrosine kinase EPH A2 (EphA2) is commonly observed in aggressive breast cancer and correlates with a poor prognosis. However, while EphA2 has been reported to enhance tumorigenesis, proliferation, MAPK activation several model systems, other studies suggest that diminishes these processes inhibits activity upon ligand stimulation. In this study, we eliminated expression 2 transgenic mouse models mammary carcinoma. deficiency impaired tumor initiation...

One arising challenge in the treatment of breast cancer is development therapeutic resistance to trastuzumab, an antibody targeting human epidermal growth factor receptor-2 (HER2), which frequently amplified cancers. In this study, we provide evidence that elevated level receptor tyrosine kinase Eph A2 (EphA2) important contributor trastuzumab resistance. a screen large cohort cancers, found EphA2 overexpression correlated with decrease disease-free and overall survival HER2-overexpressing...

Angiogenesis is critical for vascular remodeling during development and contributes to the pathogenesis of diseases such as cancer. Targeted disruption several EphB class receptor tyrosine kinases results in defects embryogenesis. The role EphA receptors remodeling, however, not well-characterized. We recently demonstrated that global inhibition disrupts endothelial migration induced by ephrin, VEGF or tumor-derived signals, though specific target remained undefined. Here, we report EphA2...

To determine if Neu is dominant over transforming growth factor beta (TGF-beta), we crossed mouse mammary tumor virus (MMTV)-Neu mice with MMTV-TGF-beta1(S223/225) expressing active TGF-beta1 in the gland. Bigenic (NT) and Neu-induced tumors developed a similar latency. The bigenic their metastases were less proliferative than those occurring MMTV-Neu mice. However, NT exhibited apoptosis more locally invasive of higher histological grade. circulating cells lung mice, while contained levels...

Breast cancers that occur in women 2-5 years postpartum are more frequently diagnosed at metastatic stages and correlate with poorer outcomes compared breast young, premenopausal women. The molecular mechanisms underlying the malignant severity associated (ppBCs) unclear but relate to stromal wound-healing events during involution, a dynamic process characterized by widespread cell death milk-producing mammary epithelial cells (MECs). Using both spontaneous allografted tumors fully...

Pre-clinical studies provide compelling evidence that Eph family receptor tyrosine kinases (RTKs) and ligands promote cancer growth, neovascularization, invasion, metastasis. Tumor suppressive roles have also been reported for the receptors, however, creating a potential barrier clinical application. Determining how these observations relate to outcome is crucial step translating biological mechanistic data into new molecularly targeted therapies. We investigated eph ephrin expression in...

Genome-wide analyses determined previously that the receptor tyrosine kinase (RTK) EPHA2 is commonly overexpressed in non-small cell lung cancers (NSCLCs). overexpression associated with poor clinical outcomes; therefore, may represent a promising therapeutic target for patients NSCLC. In support of this hypothesis, here we have shown targeted disruption EphA2 murine model aggressive Kras-mutant NSCLC impairs tumor growth. Knockdown human lines reduced growth and viability, confirming...

Clinical translation of therapies based on small interfering RNA (siRNA) is hampered by siRNA's comprehensively poor pharmacokinetic properties, which necessitate molecule modifications and complex delivery strategies. We sought an alternative approach to commonly used nanoparticle carriers leveraging the long-lived endogenous serum protein albumin as siRNA carrier. synthesized conjugated a diacyl lipid moiety (siRNA-L2), rapidly binds in situ. siRNA-L2, comparison with unmodified siRNA,...

By activating the transcription cofactors YAP and TAZ, receptor EphA2 mediates a metabolic switch to glutamine dependency in HER2 + breast cancers.

Abstract Ephrin-A1, the prototypic ligand for EphA receptor tyrosine kinases, is overexpressed in vascularized tumors relative to normal tissue. Moreover, ephrin-A1-Fc fusion proteins induce endothelial cell sprouting, migration, and assembly vitro, s.c. vascular remodeling vivo. Based on these data, we hypothesized that native, membrane-bound ephrin-A1 regulates tumor angiogenesis progression. We tested this hypothesis using a transplantable mouse mammary model. Small interfering...

Angiogenesis, the process by which new blood vessels are formed from preexisting vasculature, is critical for vascular remodeling during development and contributes to pathogenesis of diseases such as cancer. Prior studies our laboratory demonstrate that EphA2 receptor tyrosine kinase a key regulator angiogenesis in vivo. The EphA receptor-mediated angiogenic response dependent on activation Rho family GTPase Rac1 regulated phosphatidylinositol 3-kinase. Here we report identification Vav2...

EphA2 belongs to a unique family of receptor tyrosine kinases that play critical roles in development and disease. Since is required for ephrin-A1 ligand-induced vascular remodeling overexpressed variety vascularized human adenocarcinomas, we assessed tumor angiogenesis metastatic progression EphA2-deficient host animals. 4T1 mammary adenocarcinoma cells transplanted subcutaneously orthotopically into female mice displayed decreased volume, cell survival, microvascular density, lung...

EphA2 is a member of the Eph family receptor tyrosine kinases. mediates cell-cell communication and plays critical roles in number physiological pathologic responses. We have previously shown that key regulator tumor angiogenesis phosphorylation regulates signaling. To understand role phosphorylation, we mapped phosphorylated tyrosines within intracellular region by combination mass spectrometry analysis phosphopeptide mapping using two-dimensional chromatography conjunction with...

Abstract Microenvironmental cues instruct infiltrating tumor-associated myeloid cells to drive malignant progression. A subpopulation of coexpressing endothelial and markers, although rare in peripheral blood, are primarily associated with tumors where they enhance tumor growth angiogenesis. These biphenotypic vascular leukocytes result from the differentiation progenitors, a process regulated by necrosis factor (TNF)α vitro. An vivo increase tumor-derived TNFα expression promoted...

Basal-like/triple-negative breast cancers (TNBCs) are among the most aggressive forms of cancer, and disproportionally affects young premenopausal women African descent. Patients with TNBC suffer a poor prognosis due in part to lack molecularly targeted therapies, which represents critical barrier for effective treatment. Here, we identify EphA2 receptor tyrosine kinase as clinically relevant target TNBC. expression is enriched basal-like molecular subtype human cancers. Loss function both...

HER2 overexpression drives Akt signaling and cell survival HER2-enriched breast tumors have a poor outcome when is upregulated. activated by phosphorylation at T308 via PI3K S473 mTORC2. The importance of PI3K-activated well documented in HER2-amplified cancer models, but the significance mTORC2-activated this setting remains uncertain. We report here that mTORC2 obligate cofactor Rictor enriched samples, correlating with increased on Akt. In invasive specimens, expression was upregulated...

Recent genome-wide analyses in human lung cancer revealed that EPHA2 receptor tyrosine kinase is overexpressed non-small cell (NSCLC), and high levels of correlate with poor clinical outcome. However, the mechanistic basis for EPHA2-mediated tumor promotion remains poorly understood. Here, we show JNK/c-JUN signaling mediates EPHA2-dependent proliferation motility. A screen phospho-kinase arrays a decrease phospho-c-JUN knockdown cells. Knockdown inhibited p-JNK p-c-JUN approximately 50%...

The importance of the mTOR complex 2 (mTORC2) signaling in tumor progression is becoming increasingly recognized. HER2-amplified breast cancers use Rictor/mTORC2 to drive formation, cell survival and resistance human epidermal growth factor receptor (HER2)-targeted therapy. Cell motility, a key step metastatic process, can be activated by mTORC2 luminal triple negative cancer lines, but its role promoting metastases from not yet clear.Because Rictor an obligate cofactor mTORC2, we...

Abstract Dysregulation of receptor tyrosine kinases (RTK) contributes to cellular transformation and cancer progression by disrupting key metabolic signaling pathways. The EPHA2 RTK is overexpressed in aggressive forms breast cancer, including the HER2+ subtype, correlates with poor prognosis. However, role tumor metabolism remains unexplored. In this study, we used vivo vitro models HER2-overexpressing investigate mechanisms which ligand–independent promotes tumorigenesis absence its...

Small-molecule inhibitors of the mTORC2 kinase (torkinibs) have shown efficacy in early clinical trials. However, torkinibs under study also inhibit other mTOR-containing complex mTORC1. While mTORC1/mTORC2 combined inhibition may be beneficial cancer cells, recent reports describe compensatory cell survival upon mTORC1 due to loss negative feedback on PI3K, increased autophagy, and macropinocytosis. Genetic models suggest that selective would effective breast cancers, but lack...

Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates diverse array cellular processes, including cell growth, survival, metabolism, and cytoskeleton dynamics. mTOR functions in two distinct complexes, mTORC1 mTORC2, whose activities substrate specificities are regulated by complex specific cofactors, Raptor Rictor, respectively. Little known regarding the relative contribution versus mTORC2 vascular endothelial cells. Using mouse models or Rictor gene targeting,...