Cancer is the second cause of death worldwide, constituting a crucial medical and socio-economic challenge. Gene/environment interactions play a pivotal role in the development of cancer. Environmental pollutants, several of which act as endocrine disruptors (EDs) may interact with genetic background to increase the risk and modulate aggressiveness of many different cancers, including endocrine-related breast (BC) cancer.
This project aims at dissecting the complex interplay between BC genomic landscape and exposure to EDs by:
1. Defining the molecular mechanisms of action of selected EDs in genetically defined preclinical models of BC in vitro (WP1);
2. Understanding the role of EDs in tumor development and progression in vivo employing different mouse models of BC (WP2);
The overall aim of the project is to identify driver mechanisms/molecular mediators through which EDs exert their tumor-promoting activity; potentially actionable genetic alterations/signaling pathways could be then exploited to develop targeted prevention/treatment strategies aimed at reversing such tumor-promoting effects. The proposed experimental strategies aim at validating potential candidates identified by literature and our preliminary data on one hand, and discovery-based identification of new potential candidates, using integrated approaches in preclinical models in vitro and in vivo. Finally, in vitro and in vivo models will recapitulate the entire process from pre-neoplastic changes to overt tumor progression, potentially allowing for translation of the results achieved in a preventive setting.
Altogether, this project will propose several innovations, by linking external sources of exposure to biomarkers, disease phenotypes, and potential molecular targets, which could be widely exploited in diagnostic, therapeutic, preventive and health-economic applications.
This project will propose important innovations, as it will show a relationship between EDs and genomic aberration. The subpopulation of patients with HER2-positive BC accounts for 20% of all BCs and, according to the latest Airtum report, about 8000 women were affected by HER2-positive BC in Italy in 2020. If the correlation between EDs and HER2-positive BC and the effect of lifestyle directives is demonstrated, it will be possible to launch promotional campaigns for prevention on the national territory. All this would lead to a significant reduction in the diagnosis of HER2-positive BC, a tumor biology that requires very expensive treatments both in early and advanced setting; all this increases the interest in prevention, as we aim at demonstrating in this project.
Experimental models such as GEMMs and xenografts in immunocompromised mice represent key tools in elucidating cancer development and progression. In addition, they might serve as a surrogate for patients in the evaluation of the effects of EDs in tumor development. Accordingly, tumors spontaneously growing in GEMMs represent a suitable experimental modality to test biological effects of EDs in fully immunocompetent hosts. In agreement with that the analysis of EDs effects in BC GEMMs can provide helpful results and might predict their effects in humans. The short mice gestation and life span might consent fast breeding of a large number of animals and, thus the possibility of several experiments in a fairly brief interval. One of the aims of this project to correlate findings obtained in animal models with those obtained in humans.
Additionally, the identification of circulating biomarkers, as miRNAs, related to presence of EDs contaminants, to the development of BC and to the occurrence of metastases could provide clinicians with valuable biomarkers capable to rapidly and specifically assess the presence of a high-risk condition and to predict the patient¿s risk for cancer or metastasis development. Indeed, circulating miRNA signatures are promising diagnostic biomarkers for: 1) high specificity (indeed miRNAs are known to be highly tissue- and cell-specific), 2) reduced costs analysis, 3) the analysis is minimally invasive requiring a routinely available plasma sample, 4) rapidity, high specificity and good sensitivity of their dosage, 5) possibility to repeat the test with a high frequency, thus being appropriate for longitudinal studies. Of note, miRNAs expression is rapidly and finely modulated in response to cellular changes, endogenous signals and/or environmental stimuli, thus representing useful biomarkers for a step-by-step monitoring of response to anti-cancer therapies. The analyses will generate large datasets that could be processed by artificial intelligence approaches (e.g. machine learning and network medicine), that could lead to identify novel pathogenetic, diagnostic, and therapeutic targets for a tailored, personalized therapeutic approach, which might further improve therapy in terms of efficacy and QOL.
Eventual Project's results will significantly contribute to the broader objective of advancing the knowledge on molecular pathways linked to the onset and progression of different cancer types, as well as to help developing new therapeutic approaches.
Finally, in order to effectively achieve the proposed Project's objectives, shared research platforms will be created or implemented, which could be made available to subsequent investigations of the proponents' group, to external researchers, or to scientific community at large.