DNA-repair defects in pancreatic neuroendocrine tumors and potential clinical applications

Liu, Iris H.; Ford, James M.; Kunz, Pamela L.

doi:10.1016/j.ctrv.2015.11.006

Cited by 15 publications

(9 citation statements)

References 92 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…If DNA damage is too severe, without repair, the cell will enter one of the following states: senescence, apoptosis or necrosis. There are several important repair pathways for DNA including mismatch repair (MMR), nucleotide excision repair (NER), and base excision repair (BER), and homologous recombination (HR) pathways (Liu et al;. A number of anticancer drugs induce extensive DNA damage that can lead to cell cycle arrest and eventually cell death.…”

Section: Activation Of Dna Repair Mechanismsmentioning

confidence: 99%

Resveratrol as MDR reversion molecule in breast cancer: An overview

Alamolhodaei

Tsatsakis

Ramezani

et al. 2017

Food and Chemical Toxicology

View full text Add to dashboard Cite

Breast cancer is the most common cause of cancer mortality among women worldwide; therefore, a strategy to defeat breast cancer is an extremely important medical issue. One of the major challenges in this regard is multidrug resistance (MDR). Resveratrol, a well-known phytoestrogen, may be helpful as part of an overall strategy to defeat breast cancer. The mixed agonist and antagonist role of resveratrol for the estrogen receptor makes it a controversial but interesting molecule in cancer therapy, especially in hormone dependent cancers. Several in vitro investigations have suggested that resveratrol can reverse multidrug resistance. However, poor bioavailability of resveratrol is a potential limitation for resveratrol treatment and cancer outcome in vivo. Fortunately, combination therapy with other selected compounds improves resveratrol's bioavailability and/or a delay in its metabolism. This review summaries the available published literature dealing with the effects of resveratrol on multidrug resistance in cancer and more specifically, breast cancer.

show abstract

Section: Activation Of Dna Repair Mechanismsmentioning

confidence: 99%

Resveratrol as MDR reversion molecule in breast cancer: An overview

Alamolhodaei

Tsatsakis

Ramezani

et al. 2017

Food and Chemical Toxicology

View full text Add to dashboard Cite

show abstract

“…Additionally, an mTOR inhibitor, everolimus, is used to treat PanNET patients. Phosphatase and tensin homolog (PTEN), a key negative regulator of the PI3K/AKT/mTOR pathway, is frequently mutated or lost in several familial or sporadic cancer types; however, in PanNETs, the frequency of loss is low, 7-26.4% [21,[32][33][34][35][36][37][38]. Co-mutations of MEN1 and PTEN have been observed in a small percentage of human PanNETs [21,32].…”

Section: Introductionmentioning

confidence: 99%

Two well-differentiated pancreatic neuroendocrine tumor mouse models

et al. 2019

View full text Add to dashboard Cite

Multiple endocrine neoplasia type 1 (MEN1) is a genetic syndrome in which patients develop neuroendocrine tumors (NETs), including pancreatic neuroendocrine tumors (PanNETs). The prolonged latency of tumor development in MEN1 patients suggests a likelihood that other mutations cooperate with Men1 to induce PanNETs. We propose that Pten loss combined with Men1 loss accelerates tumorigenesis. To test this, we developed two genetically engineered mouse models (GEMMs)-MPR (Men1 flox/flox Pten flox/flox RIP-Cre) and MPM (Men1 flox/flox Pten flox/flox MIP-Cre) using the Cre-LoxP system with insulin-specific biallelic inactivation of Men1 and Pten. Cre in the MPR mouse model was driven by the transgenic rat insulin 2 promoter while in the MPM mouse model was driven by the knock-in mouse insulin 1 promoter. Both mouse models developed well-differentiated (WD) G1/G2 PanNETs at a much shorter latency than Men1 or Pten single deletion alone and exhibited histopathology of human MEN1-like tumor. The MPR model, additionally, developed pituitary neuroendocrine tumors (PitNETs) in the same mouse at a much shorter latency than Men1 or Pten single deletion alone as well. Our data also demonstrate that Pten plays a role in NE tumorigenesis in pancreas and pituitary. Treatment with the mTOR inhibitor rapamycin delayed the growth of PanNETs in both MPR and MPM mice, as well as the growth of PitNETs, resulting in prolonged survival in MPR mice. Our MPR and MPM mouse models are the first to underscore the cooperative roles of Men1 and Pten in cancer, particularly neuroendocrine cancer. The early onset of WD PanNETs mimicking the human counterpart in MPR and MPM mice at 7 weeks provides an effective platform for evaluating therapeutic opportunities for NETs through targeting the MENIN-mediated and PI3K/AKT/mTOR signaling pathways.

show abstract

“…Studies have shown that up to 36% of panNET cases have MLH1 loss. One mechanism by which this occurs is hypermethylation of the gene [ 14 , 15 ]. Mei et al studied 55 sporadic insulinomas and showed that 20 (36%) showed reduced expression of MLH1 (defined as <25% positive with IHC staining) or loss of MLH1 (determined with IHC), which corresponded to a 33% rate of MSI-H [ 16 ].…”

Section: Discussionmentioning

confidence: 99%

Microsatellite Instability-High, Malignant Insulinoma With Brain Metastasis

Starr

Puebla²,

McMillan³

et al. 2021

Cureus

View full text Add to dashboard Cite

Insulinomas are the most common type of functional pancreatic neuroendocrine tumor. Although insulinomas usually are noninvasive or benign, 10% are deemed invasive or malignant. The pathologic mechanisms that lead to the malignant phenotype are not well elucidated. In this case report, we present a patient with stage 4 malignant insulinoma with metastasis to the liver, bone, and brain. Genetic analysis of the tumor showed that the tumor was mismatch-repair deficient and had a high rate of microsatellite instability. There was loss of MLH1 - and PMS2 -encoded protein expression, and MLH1 and MEN1 variants were identified. Notably, the liver metastasis showed considerable tumor heterogeneity (well differentiated) compared with the brain metastasis (poorly differentiated).

show abstract

DNA-repair defects in pancreatic neuroendocrine tumors and potential clinical applications

Cited by 15 publications

References 92 publications

Resveratrol as MDR reversion molecule in breast cancer: An overview

Resveratrol as MDR reversion molecule in breast cancer: An overview

Two well-differentiated pancreatic neuroendocrine tumor mouse models

Microsatellite Instability-High, Malignant Insulinoma With Brain Metastasis

Contact Info

Product

Resources

About