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- Analysis of mutational allelic imbalances’ Influence on drug treatment responsePublication . Fontes, Melissa Ferreira; Maia, Ana-Teresa; Ferreira, Bibiana I.Breast cancer exhibits significant heterogeneity across various dimensions concerning histological and molecular classification, as well as mutational profile and clinical outcome. Defining treatment courses is likewise a complex task, as patients share similar features but different clinical prognoses. Nowadays, prognostic assessment tries to capture the morphologic and genetic variation within breast tumours, employing a variety of multigene molecular tests focusing on measuring gene expression of a specific gene panel, to predict patient outcome. In current clinical practice, the assessment of the PIK3CA mutational status is a routine procedure for hormone-receptor positive, HER2 negative metastatic breast cancers. Evaluation of gain-of-function mutations in the PIK3CA gene within this patient cohort helps to identify individuals who may benefit from systemic treatment with alpelisib, a PI3Kα-specific inhibitor. Previous studies have demonstrated that widespread allelic imbalances in the expression of somatic mutations in PIK3CA are associated with prognosis in breast cancer. Particularly, preferential expression of PIK3CA’s mutated allele is associated with poorer prognosis. Here, we hypothesise that differential allelic expression of PIK3CA mutations influences protein levels in breast cancer cells, thereby potentially affecting drug treatment response. We aimed to create an inducible PIK3CA breast cell-based tool capable of inducing different levels of PIK3CA mutational expressions as a platform to evaluate the impact of mutational expression levels on the response to PI3K-targeted therapies. Our goal was to create a cell-based system to precisely identify patients eligible for PI3K-α inhibitor therapies by modelling PIK3CA mutant expression dosages and assessing cell drug response. Our results show that we successfully generated a plasmid capable of constitutively expressing the wild-type isoform of the PIK3CA gene and also three inducible plasmids that can express three different levels of each PIK3CA mutant in a controlled manner. These plasmids constitute the tools required to transfect breast cell lines and generate the PIK3CA inducible system. Once the system is not yet created, our hypothesis is still subject to proof.