PTEN breast cancer susceptibility: a matter of dose
1Laboratory of Experimental Oncology, Oncology Institute of Southern Switzerland, via Vela 6, 6500 Bellinzona, Switzerland.
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].
Insights
Phosphatase and tensin homolog (PTEN) protein down-regulation, not mutations, is common in breast tumors. This finding highlights PTEN
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene frequently mutated in human cancers.
- PTEN regulates the AKT/PKB pathway by converting PIP3 to PIP2.
- While PTEN mutations are linked to Cowden syndrome and breast cancer susceptibility, its role in sporadic breast cancer was considered minor.
Purpose of the Study:
- To investigate the role of PTEN gene dosage in breast cancer development.
- To challenge the dogma regarding PTEN's minor role in sporadic breast tumorigenesis.
- To explore novel clinical and therapeutic implications of PTEN's function in breast cancer.
Main Methods:
- Analysis of PTEN mutations and deletions in sporadic breast tumors.
- Assessment of PTEN protein down-regulation frequency in breast tumors.
- Review of existing literature and recent findings on PTEN in breast cancer.
Main Results:
- PTEN mutations or deletions are uncommon in sporadic breast tumors (<5%).
- PTEN protein down-regulation is frequently observed ( >50%) in sporadic breast tumors.
- Evidence suggests PTEN gene dosage, not just mutations, is crucial for breast cancer susceptibility.
Conclusions:
- PTEN protein down-regulation plays a significant role in sporadic breast cancer pathogenesis.
- The study challenges previous assumptions about PTEN's limited role in breast tumorigenesis.
- Findings open new avenues for clinical and therapeutic strategies targeting PTEN in breast cancer.
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