Subtle variations in Pten dose determine cancer susceptibility

By A. Alimonti, Arkaitz Carracedo, J. Clohessy, L. Trotman, C. Nardella, Ainara Egia, L. Salmena, K. Sampieri, W. Haveman, E. Brogi and 3 more. Nature Genetics, 2010

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Cancer susceptibility has been attributed to at least one heterozygous genetic alteration in a tumor suppressor gene (TSG). It has been hypothesized that subtle variations in TSG expression can promote cancer development. However, this hypothesis has not yet been definitively supported in vivo. Pten is a TSG frequently lost in human cancer and mutated in inherited cancer-predisposition syndromes. Here we analyze Pten hypermorphic mice (Ptenhy/+), expressing 80% normal levels of Pten. Ptenhy/+ mice develop a spectrum of tumors, with breast tumors occurring at the highest penetrance. All breast tumors analyzed here retained two intact copies of Pten and maintained Pten levels above heterozygosity. Notably, subtle downregulation of Pten altered the steady-state biology of the mammary tissues and the expression profiles of genes involved in cancer cell proliferation. We present an alterative working model for cancer development in which subtle reductions in the dose of TSGs predispose to tumorigenesis in a tissue-specific manner.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/961a9f6411677ab48e00b20c03b880338fc53a0d

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Citations in the corpus

MicroRNA sponges: progress and possibilities. (2010, background): “The recent finding that reduction in the expression of a tumor suppressor by a mere 20% can promote the development of cancer (Alimonti et al. 2010) suggests that screens with sponges, which may alter target gene expression to a similar extent, could be generally informative.”
Cellular Senescence: Aging, Cancer, and Injury. (2019, background): “Ionizing radiation can also induce senescence in different cancer cell lines (11, 120, 260).”
Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs (2011, unknown): “…of human cancers (Hollander et al., 2011), (2) subtle changes in PTEN dose dictate critical outcomes in tumor initiation and progression in vivo (Alimonti et al., 2010; Berger et al., 2011; Trotman et al., 2003), and (3) numerous microRNAs have beenvalidatedasPTENregulators, including…”
A saturation mutagenesis approach to understanding PTEN lipid phosphatase activity and genotype-phenotypes relationships (2018, background): “9,10 In mice, loss of this activity increases tumor susceptibility in a dosedependent manner.(11) This observation led to a continuum model for PTEN’s role in cancer development, with the level of phenotypic severity tightly coupled to the level of lipid phosphatase activity.”
Phosphoinositides: tiny lipids with giant impact on cell regulation. (2013, background): “Remarkably, a dose-dependent reduction in PTEN even above monozygocity is associated with increased tumor formation (31, 1578).”
Lifetime Cancer Risks in Individuals with Germline PTEN Mutations (2012, background): “The effect of reduced PTEN protein dose on cancer susceptibility has been shown both in animal models (18) and recently, in humans (9).”
PTEN loss in the continuum of common cancers, rare syndromes and mouse models (2011, unknown): “In mice, decreasing PTEN dosage correlates with increasing tumour susceptibilit”