The PI3K/AKT/mTOR Pathway as a Therapeutic Target in Endometrial Cancer

Slomovitz, Brian M.; Coleman, Robert L.

doi:10.1158/1078-0432.ccr-12-0662

Cited by 347 publications

(282 citation statements)

References 85 publications

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“…Activation of the PI3K/AKT/mTOR pathway, a signaling pathway that plays an important role in cellular growth and survival, has recently been implicated in endometrial cancer (32). Activated AKT initiates a cascade of downstream signaling events in endometrial cancer cells that promote cellular growth, metabolism, proliferation, survival, migration, apoptosis, and angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Pigment Epithelium–Derived Factor Alleviates Tamoxifen-Induced Endometrial Hyperplasia

Goldberg

Bar‐Joseph

Grossman

et al. 2015

Molecular Cancer Therapeutics

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Tamoxifen is a cornerstone component of adjuvant endocrine therapy for patients with hormone-receptor-positive breast cancer. Its significant adverse effects include uterine hyperplasia, polyps, and increased risk of endometrial cancer. However, the underlying molecular mechanism remains unclear. Excessive angiogenesis, a hallmark of tumorigenesis, is a result of disrupted balance between pro-and anti-angiogenic factors. VEGF is a proangiogenic factor shown to be elevated by tamoxifen in the uterus. Pigment epithelium-derived factor (PEDF) is a potent anti-angiogenic factor that suppresses strong pro-angiogenic factors, such as VEGF. Our aim was to investigate whether angiogenic balance plays a role in tamoxifen-induced uterine pathologies, elucidate the molecular impairment in that network, and explore potential intervention to offset the proposed imbalance elicited by tamoxifen. Using in vivo mouse models, we demonstrated that tamoxifen induced a dose-dependent shift in endogenous uterine angiogenic balance favoring VEGF over PEDF. Treatment with recombinant PEDF (rPEDF) abrogated tamoxifen-induced uterine hyperplasia and VEGF elevation, resulting in reduction of blood vessels density. Exploring the molecular mechanism revealed that tamoxifen promoted survival and malignant transformation pathways, whereas rPEDF treatment prevents these changes. Activation of survival pathways was decreased, demonstrated by reduction in AKT phosphorylation concomitant with elevation in JNK phosphorylation. Estrogen receptor-a and c-Myc oncoprotein levels were reduced. Our findings provide novel insight into the molecular mechanisms tamoxifen induces in the uterus, which may become the precursor events of subsequent endometrial hyperplasia and cancer. We demonstrate that rPEDF may serve as a useful intervention to alleviate the risk of tamoxifen-induced endometrial pathologies.

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Section: Discussionmentioning

confidence: 99%

Pigment Epithelium–Derived Factor Alleviates Tamoxifen-Induced Endometrial Hyperplasia

Goldberg

Bar‐Joseph

Grossman

et al. 2015

Molecular Cancer Therapeutics

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“…In this cross-talk mechanism, regulation of tumor growth by the ER-pathway could be activated by another type of RTK signaling that is commonly seen in other types of hormonal sensitive malignancies such as breast and endometrial cancer [30,31]. Our data showed that there was no correlation between estrogen receptor and other RTK expressions (EGFR and HER2) but this was only determined by protein expression in immunohistochemistry study and was limited with regard to the number of RTKs analyzed.…”

Section: Discussionmentioning

confidence: 99%

Estrogen receptor expression and increased risk of lymphovascular space invasion in high-grade serous ovarian carcinoma

Matsuo

Todd

Yoshino

et al. 2013

Gynecologic Oncology

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Objective-Recent studies have demonstrated that lymphovascular space invasion (LVSI) is associated with increased risk of hematogenous and lymphatic metastasis and poor clinical outcome of women with epithelial ovarian cancer. Given the suspected role of estrogen in promoting ovarian cancer metastasis, we examined potential links between estrogen receptor and LVSI in high-grade serous ovarian carcinoma.Methods-Tumoral expression of ER, PR, p53, MDR1, EGFR, HER2, DNA ploidy, and S-phase fraction was examined for 121 cases of stage I-IV high-grade serous ovarian carcinoma samples obtained at primary cytoreductive surgery. Biomarker expression was correlated to LVSI and survival outcomes.Results-LVSI was observed in 101 (83.5%) of all cases. Immunohistochemistry of tested biomarkers showed ER (86.7%) to be the most commonly expressed followed by p53 (71.4%), Conclusion-Our data demonstrated that estrogen receptor was positively correlated with LVSI that was an independent prognostic indicator of poor survival outcomes of high-grade serous ovarian carcinoma. This study emphasizes the importance of estrogen pathway in promoting lymphatic or vascular spread of high-grade serous ovarian carcinoma.

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“…Downstream targets of mTOR include p70 ribosomal protein 6S kinase (S6K). The overactivation of the PI3K/Akt/mTOR pathway, a signaling pathway that plays a key role in cellular growth and survival, has been implicated in various tumor pathogeneses, and as such, the inhibition of the PI3K/Akt/mTOR pathway is of therapeutic interest [112][113][114]. Medici and Olsen [39] found that HemECs had constitutively active PI3K/Akt/ mTOR/p70S6K and tested their hypothesis that these cells could be sensitive to mTOR inhibitors (e.g., rapamycin).…”

Section: Hif-α-mediated Pathwaymentioning

confidence: 99%

Wnt3a Expression is Associated with MMP-9 Expression in Primary Tumor and Metastatic Site in Recurrent or Stage IV Colorectal Cancer

2014

Cancer Cell Signaling

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Infantile hemangioma (IH), which is the most common tumor in infants, is a benign vascular neoplasm resulting from the abnormal proliferation of endothelial cells and pericytes. For nearly a century, researchers have noted that IH exhibits diverse and often dramatic clinical behaviors. On the one hand, most lesions pose no threat or potential for complication and resolve spontaneously without concern in most children with IH. On the other hand, approximately 10% of IHs are destructive, disfiguring and even vision-or life-threatening. Recent studies have provided some insight into the pathogenesis of these vascular tumors, leading to a better understanding of the biological features of IH and, in particular, indicating that during hemangioma neovascularization, two main pathogenic mechanisms prevail, angiogenesis and vasculogenesis. Both mechanisms have been linked to alterations in several important cellular signaling pathways. These pathways are of interest from a therapeutic perspective because targeting them may help to reverse, delay or prevent hemangioma neovascularization. In this review, we explore some of the major pathways implicated in IH, including the VEGF/VEGFR, Notch, β-adrenergic, Tie2/angiopoietins, PI3K/AKT/mTOR, HIF-α-mediated and PDGF/PDGF-R-β pathways. We focus on the role of these pathways in the pathogenesis of IH, how they are altered and the consequences of these abnormalities. In addition, we review the latest preclinical and clinical data on the rationally designed targeted agents that are now being directed against some of these pathways.

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The PI3K/AKT/mTOR Pathway as a Therapeutic Target in Endometrial Cancer

Abstract: Endometrial cancer is the most common gynecologic malignancy in the United States.

Cited by 347 publications

References 85 publications

Pigment Epithelium–Derived Factor Alleviates Tamoxifen-Induced Endometrial Hyperplasia

Pigment Epithelium–Derived Factor Alleviates Tamoxifen-Induced Endometrial Hyperplasia

Estrogen receptor expression and increased risk of lymphovascular space invasion in high-grade serous ovarian carcinoma

Wnt3a Expression is Associated with MMP-9 Expression in Primary Tumor and Metastatic Site in Recurrent or Stage IV Colorectal Cancer

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