Abstract
The characterization of tumor biology and consequently the identification of prognostic and predictive biomarkers represent key issues for the translational research in breast cancer (BC). Phosphatase and tensin homolog deleted on chromosome ten (PTEN), the negative regulator of the proto-oncogenic phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) pathway, constitutes one of the most intriguing tumor suppressor genes involved in a series of biological processes, such as cell growth and survival, cellular migration and genomic stability. Loss of PTEN activity, due to protein, genetic or epigenetic alterations, was reported in up to almost half of BC cases. Recently, besides the role of PTEN in the pathogenesis of BC, investigated for over 20 years after the PTEN discovery, several retrospective and prospective translational studies, in the early and advanced setting, reported controversial results regarding the association between PTEN functional status and both clinical outcome and response to various BC treatments. This review explores the pre-clinical and clinical role of PTEN in BC with regard to the potential association of PTEN with prognosis and treatment response or resistance, underlying the complexity of the interpretation of available results and suggesting potential future perspectives.
Highlights
In the recent era of precision medicine, translational and clinical research have been matched together with enormous efforts in order to characterize tumors and customize treatment according to genetic, epigenetic or proteomic alterations
In the PAKT trial, Schmid et al reported that the progression-free survival (PFS) prolongation observed with Capivasertib plus Paclitaxel versus Paclitaxel plus placebo in triple-negative metastatic breast cancer (BC) was mainly driven by the PIK3CA/Akt1/PTEN-altered population, since no beneficial effect from the addition of Capivasertib to Paclitaxel was observed in patients with PIK3CA/Akt1/PTEN non-altered tumors [39]
There is some evidence for an association between PTEN functional status and both clinical outcome and response to various treatments, robust evidence is missing to properly establish its actual prognostic and/or predictive role in BC
Summary
In the recent era of precision medicine, translational and clinical research have been matched together with enormous efforts in order to characterize tumors and customize treatment according to genetic, epigenetic or proteomic alterations. In the context of breast cancer (BC), the integration between technology, innovation and translational research represents a key issue to understand tumor biology and to identify potential biomarkers of drug response or resistance In this regard, phosphatase and tensin homolog deleted on chromosome ten (PTEN) represents one of the most frequently altered genes in human cancer, including BC. The post-translational modifications of wild-type PTEN (e.g., phosphorylation, mono- or poly-ubiquitination, sumoylation, oxidation and acetylation) are known to tightly regulate the function of the tumor suppressor as the result of altered subcellular localization, protein/protein interaction and/or phosphatase activity, independently of PTEN accumulation [10] This process might explain some discrepancies related to PTEN expression levels, evaluated by next-generation sequencing or immunohistochemistry, and its biological functions. 1 (PD-L1) expression and PD-L1 transcript in triple-negative BC cell lines, resulting, at the functional level, in decreased T-cell proliferation and increased T-cell apoptosis, as suggested by co-culture experiments [26]
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