Targeting Signaling Pathways in Epithelial Ovarian Cancer

Smolle, Elisabeth; Taucher, Valentin; Pichler, Martin; Petru, Edgar; Lax, Sigurd; Haybaeck, Johannes

doi:10.3390/ijms14059536

Cited by 54 publications

(54 citation statements)

References 105 publications

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“…EGFR is a receptor tyrosine kinase (RTK) whose activation by ligand binding (such as EGF, amphiregulin, TGFa) contributes to cancer cell proliferation, invasion, and metastasis. EGFR activation and signaling are leading causes of malignancy in many types of cancer such as breast, lung, metastatic colorectal, head and neck, ovarian, and brain cancers (2)(3)(4)(5)(6)(7). Notably, in breast cancers, EGFR is expressed by triple-negative breast cancers (TNBC) or basal-like breast cancers, which are highly aggressive cancers with a high rate of early-occurring lung and brain metastasis.…”

Section: Introductionmentioning

confidence: 99%

EGFR Activation and Signaling in Cancer Cells Are Enhanced by the Membrane-Bound Metalloprotease MT4-MMP

et al. 2014

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MT4-MMP (MMP-17) is a glycosylphosphatidyl inositol-anchored matrix metalloprotease expressed on the surface of cancer cells that promotes tumor growth and metastasis. In this report, we identify MT4-MMP as an important driver of cancer cell proliferation through CDK4 activation and retinoblastoma protein inactivation. We also determine a functional link between MT4-MMP and the growth factor receptor EGFR. Mechanistic experiments revealed direct association of MT4-MMP and its positive effects on EGFR phosphorylation in response to TGFa and EGF in cancer cells. Notably, the effects of MT4-MMP on proliferation and EGFR activation did not rely on metalloprotease activity. Clinically, MT4-MMP and EGFR expressions were correlated in human triple-negative breast cancer specimens. Altogether, our results identify MT4-MMP as a positive modifier of EGFR outside-in signaling that acts to cooperatively drive cancer cell proliferation. Cancer Res; 74(23); 6758-70. Ó2014 AACR.

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Section: Introductionmentioning

confidence: 99%

EGFR Activation and Signaling in Cancer Cells Are Enhanced by the Membrane-Bound Metalloprotease MT4-MMP

et al. 2014

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“…Consequently, very limited targeted therapies are available to treat this disease. VEGF and poly (ADP-ribose) polymerase (PARP) inhibitors show promising results, but due to the severity and late progression of most ovarian cancers at the time of diagnosis, there is an urgent need for the development of more targeted therapies (29). Here, we use a mouse model of ovarian endometrioid adenocarcinoma that depends upon concomitant activation of oncogenic Kras, and deletion of Pten (30).…”

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confidence: 99%

PI3K isoform dependence of PTEN-deficient tumors can be altered by the genetic context

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Zhang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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There has been increasing interest in the use of isoform-selective inhibitors of phosphatidylinositide-3-kinase (PI3K) in cancer therapy. Using conditional deletion of the p110 catalytic isoforms of PI3K to predict sensitivity of cancer types to such inhibitors, we and others have demonstrated that tumors deficient of the phosphatase and tensin homolog (PTEN) are often dependent on the p110β isoform of PI3K. Because human cancers usually arise due to multiple genetic events, determining whether other genetic alterations might alter the p110 isoform requirements of PTEN-null tumors becomes a critical question. To investigate further the roles of p110 isoforms in PTEN-deficient tumors, we used a mouse model of ovarian endometrioid adenocarcinoma driven by concomitant activation of the rat sarcoma protein Kras, which is known to activate p110α, and loss of PTEN. In this model, ablation of p110β had no effect on tumor growth, whereas p110α ablation blocked tumor formation. Because ablation of PTEN alone is often p110β dependent, we wondered if the same held true in the ovary. Because PTEN loss alone in the ovary did not result in tumor formation, we tested PI3K isoform dependence in ovarian surface epithelium (OSE) cells deficient in both PTEN and p53. These cells were indeed p110β dependent, whereas OSEs expressing activated Kras with or without PTEN loss were p110α dependent. Furthermore, isoform-selective inhibitors showed a similar pattern of the isoform dependence in established Kras G12D /PTEN-deficient tumors. Taken together, our data suggest that, whereas in some tissues PTEN-null tumors appear to inherently depend on p110β, the p110 isoform reliance of PTEN-deficient tumors may be altered by concurrent mutations that activate p110α.ovarian cancer | PI3K inhibitors | genetically engineered mouse model

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“…EOC represents 90% of ovarian malignant tumors (3) and is an extremely heterogeneous group of neoplasms that exhibit a wide range of tumor morphology, clinical manifestations and underlying genetic alterations (4). The most common histological type, high-grade ovarian serous carcinoma (OSC), is characterized by tumor protein p53 mutations and breast cancer 1 and 2 dysfunction (5).…”

Section: Introductionmentioning

confidence: 99%