Cowden Syndrome–Affected Patients with PTEN Promoter Mutations Demonstrate Abnormal Protein Translation

Teresi, Rosemary E.; Zbuk, Kevin; Pezzolesi, Marcus G.; Waite, Kristin; Eng, Charis

doi:10.1086/521051

Cited by 77 publications

(61 citation statements)

References 39 publications

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“…As the underlying genetic causes determining high levels of ALK expression remained to be determined in a considerable proportion of patients, we investigated whether missense mutations in the promoter sequence could account for ALK overexpression (28,29). Genomic DNA from eight cell lines and 29 patients (ALK negative/low, 9 patients; ALK moderate, 6 patients; ALK high, 14 patients) expressing wild-type ALK was subjected to sequence analysis in the 2,564-bp region upstream of the translation start codon containing the putative promoter of ALK.…”

Section: Resultsmentioning

confidence: 99%

Mutation-Independent Anaplastic Lymphoma Kinase Overexpression in Poor Prognosis Neuroblastoma Patients

Passoni¹,

Longo

Collini³

et al. 2009

Cancer Research

153

126

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Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase predominantly expressed in the developing nervous system. Recently, mutated ALK has been identified as a major oncogene associated with familial and sporadic neuroblastomas (NBL). Yet, a direct correlation between endogenous expression level of the ALK protein, oncogenic potential, and clinical outcome has not been established. We investigated ALK genetic mutations, protein expression/ phosphorylation, and functional inhibition both in NBLderived cell lines and in 34 localized and 48 advanced/ metastatic NBL patients. ALK constitutive phosphorylation/ activation was observed in high-ALK expressing cells, harboring either a mutated or a wild-type receptor. No activation was found in cell lines with low expression of wild-type ALK. After 72 hours of treatments, small molecule ALK inhibitor CEP-14083 (60 nmol/L) induced growth arrest and cell death in NBL cells overexpressing wild-type (viability: ALK high 12.8%, ALK low 73%, P = 0.0035; cell death: ALK high 56.4%, ALK low 16.2%, P = 0.0001) or mutated ALK. ALK protein expression was significantly up-regulated in advanced/metastatic compared with localized NBLs (ALK overexpressing patients: stage 1-2, 23.5%; stage 3-4, 77%; P < 0.0001). Interestingly, protein levels did not always correlate with ALK genetic alterations and/or mRNA abundance. Both mutated and wild-type ALK receptor can exert oncogenic activity in NBL cells. However, wild-type ALK receptor requires a critical threshold of expression to achieve oncogenic activation. Overexpression of either mutated or wild-type ALK defines poor prognosis patients. Alternative mechanisms other than direct mutations and/or gene amplification regulate the ALK level of expression in NBL cells. Wild-type ALK is a potential therapeutic target for advanced/metastatic NBLs.

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Section: Resultsmentioning

confidence: 99%

Mutation-Independent Anaplastic Lymphoma Kinase Overexpression in Poor Prognosis Neuroblastoma Patients

Passoni¹,

Longo

Collini³

et al. 2009

Cancer Research

153

126

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“…In this Commentary, we focus on nuclear localization of PTEN, and the importance of this in normal physiology and disease. Other nontraditional mechanisms of regulation are discussed or reviewed elsewhere (Pezzolesi et al, 2006;Teresi et al, 2007;Zbuk and Eng, 2007).…”

Section: Introductionmentioning

confidence: 99%

The nuclear affairs of PTEN

Planchon

Waite

Eng

2008

Journal of Cell Science

Self Cite

257

263

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PTEN encodes a major tumor-suppressor protein that is a dual-specificity phosphatase. Inactivation of PTEN has been shown to be involved in heritable and sporadic cancers. Mutation or deletion of PTEN, historically the most commonly identified mechanisms of inactivation of tumor suppressors, is found only in the minority of sporadic non-cultured primary cancers, which indicates that there might be other, novel mechanisms of inactivation. Despite the absence of a classic nuclear localization signal, PTEN enters the nucleus by several mechanisms, including simple diffusion, active shuttling, cytoplasmic-localization-signal-dependent export and monoubiquitylation-dependent import. Cytoplasmic PTEN has a well-known role as a negative regulator of the PI3K/AKT pathway; however, it is becoming clear that cytosolic PTEN is not the same as nuclear PTEN. Nuclear PTEN plays a role in chromosome stability, DNA repair, cell cycle arrest and cellular stability. The balance between these functions is an important factor in determining whether a cell remains benign or becomes neoplastic.

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“…Approximately, 85% of classic CS patients and 10% of Cowden-like (CSL) patients have germline PTEN mutations, with the most characterized ones being intragenic. Although proven pathogenic mutations in the promoter have been described (Zhou et al, 2003b;Teresi et al, 2007), there are many more 5 0 -UTR variations that are not well understood.…”

Section: Introductionmentioning

confidence: 99%

Differential regulation of PTEN expression by androgen receptor in prostate and breast cancers

Wang

Romigh

et al. 2011

Oncogene

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Prostate cancer and breast cancer are the most common malignancies in the western world. Androgen receptor (AR) and PTEN both have been well documented to have important roles in prostate carcinogenesis. In contrast, AR and PTEN in breast carcinogenesis have not been well studied. Furthermore, the crosstalk and connection between those two pathways remain unclear. Increased AR expression in prostate cancers, combined with decreased PTEN expression, portends a poor clinical outcome. Paradoxically, both high AR and high PTEN levels, detected by immunohistochemistry, in primary breast carcinomas have been associated with better disease-free survival. Here, we performed in silico analysis of publicly available microarray data sets from prostate or breast carcinomas. We found an inverse correlation between AR and PTEN transcript expression in prostate cancer tissues in contrast to the positive correlation in breast cancer. These data led us to hypothesize that AR may directly affect PTEN transcriptional regulation in prostate and breast cancer cells. Here, we show for the first time that AR inhibits PTEN transcription in prostate cancer cells, whereas AR upregulates PTEN transcription in breast cancer cells, which mechanistically explains both the immunohistochemical PTEN-AR expressional data noted in clinical trials and in our in silico analysis of the transcriptomes of breast and prostate cancers. In addition, we have fine-mapped the AR-binding motif within the PTEN promoter. Here we show that, in patients with Cowden syndrome, an inherited cancer syndrome caused by germline mutations scattered throughout PTEN, point variants affecting the 3 0 end of the AR-binding motif result in abrogation of androgen-mediated transcriptional regulation of PTEN expression. We may speculate that the differential AR effect on PTEN may begin to explain organ-specific and perhaps sex-specific neoplasia predisposition in Cowden syndrome, as well as why only a fraction of women with germline PTEN mutations develop breast cancer, depending on the androgen steroid milieu and levels.

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Cowden Syndrome–Affected Patients with PTEN Promoter Mutations Demonstrate Abnormal Protein Translation

Cited by 77 publications

References 39 publications

Mutation-Independent Anaplastic Lymphoma Kinase Overexpression in Poor Prognosis Neuroblastoma Patients

Mutation-Independent Anaplastic Lymphoma Kinase Overexpression in Poor Prognosis Neuroblastoma Patients

The nuclear affairs of PTEN

Differential regulation of PTEN expression by androgen receptor in prostate and breast cancers

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