PTEN breast cancer susceptibility: a matter of dose

Abstract

The phosphatase and tensin homolog located on chromosome ten, PTEN, is one of the most commonly mutated tumor suppressor genes (TSGs) in human cancer [1-3]. PTEN catalyzes the conversion of the membrane lipid second messenger PIP3 to PIP2 and is therefore a key mediator of the AKT/PKB pathway [4,5]. Although inherited PTEN mutations predispose to the development of Cowden syndrome, which is also a breast cancer susceptibility syndrome, the role of PTEN in breast tumorigenesis has been considered minor when compared to that of other TSGs such as BRCA1 or p53 [6]. There is no current evidence that mutations in PTEN account for a substantial proportion of familial breast cancer in the absence of Cowden syndrome [6]. Moreover, PTEN mutations or deletions are not common in sporadic breast tumors, especially when compared with other tumor types (<5%) such as prostate cancer [7, 8].Despite this evidence, recent studies have demonstrated that PTEN protein down-regulation is frequently observed (more than 50%) in sporadic breast tumors, highlighting the relevance of the dose of this TSG for the pathogenesis of breast cancer [7-9]. Our paper, in the last month's issue of Nature Genetics provides additional evidence of the role of PTEN dose in breast cancer susceptibility, braking current dogmas regarding the development of cancer and opening to novel clinical and therapeutic implications [10].

Figure 1:

Implications for tumorigenesis upon subtle reduction of TSG levels. The ‘no hits’ model of cancer susceptibility. The rectangular green box represents a functional allele of a given TSG. The rectangular red box represents a nonfunctional allele inactivated by, for example, mutation or deletion. The rectangular green, yellow and red box represents an allele of a TSG whose expression is reduced below the normal levels. The black rectangle represents a genetic hit. Note that the model represented does not exclude the presence of additional hits on other loci.

Figure 2:

Correlation between PTEN levels, incidence of basal-like breast tumors and treatment resistance. Note that the progressive reduction of PTEN levels is inversely correlated with the incidence of basal like breast tumors.