Project Portugal 2030

Summary

In the clinic, it is well established that enhanced mammographic density is one of the strongest risk factors for breast cancer progression. In particular, premenopausal women with dense breasts are more likely to be diagnosed with triple-negative breast cancer (TNBC) than premenopausal women with non-dense breasts. Because TNBC is characterized by unfavorable outcome due to the combination of its metastatic propensity, chemo-refractory behavior and the general lack of effective targeted interventions, to effectively treat TNBC it is urgent to identify and target the mechanisms governing TNBC progression. MINNESOTA main goal is to identify a molecular mechanism underlying ECM mechanical properties driving TNBC invasiveness and therapeutical response. To that end, we set three specific aims: I. GENERATION OF GENETIC TOOLS TO MONITOR ESR DYNAMICS IN TNBC INVASIVE CELLS (Activity 1). To accurately assess ESR dynamics in vitro, state-of the art tools will be developed. These tools will be used throughout MINNESOTA. II. ASSESSMENT OF ESR DYNAMICS DOWNSTREAM OF TNBC DECELLULARIZED ECMS (dECMS) STIFFNESS (Activity2). Here, we will establish of ECM stiffness as a key regulator of ESR-driven cell invasion in patient-derived systems. We will start by bioengineering novel in tunable biomimetic dECM/alginate-based hydrogels. Using molecular tools (Activity 1), we aim to show for the first time that there is a correlation between the mechanical properties of the ECM and ESR dynamics. Particularly, we aim to show that ESR is differently regulated by stiff ECM. III. ESTABLISHMENT OF ECM STIFFNESS AS A KEY REGULATOR OF ESR DYNAMICS IN TNBC (Activity 3). In this activity, we aim to demonstrate that ESR supports ECM stiffness-triggered cell invasion of TNBC. Together with Activities 1 and 2, this Activity will unveil the molecular mechanism underlying ECM mechano-control over ESR during invasion of TNBC cells. IV. ASSESSMENT OF ECM-DEPENDENT ESR PATHWAY CLINICAL RELEVANCE IN TNBC (Activity 4). Here we aim to identify an association between the mechanical properties of the ECM, ESR dynamics regulation and response to taxanes and ESR inhibitors. By doing so, we aim to demonstrate the potential of ESR-regulators as potential tools to predict the responses to standard chemotherapy regimens to avoid invasion and metastasis formation; and/or targets for future clinical intervention. Altogether, these activities focused on studying ECM-dependent ESR regulation in TNBC invasion will set the stage for the development of an effective clinical intervention at an early stage of TNBC and is expected to contribute to halt TNBC progression. In the future, we plan on pushing forward this research by linking our discovery-phase findings to pre-clinical studies using transplantation-based mouse models. This project aims to directly contribute to decreasing the societal (and financial) costs of clinical management of co-morbidities associated with standard chemotherapy regimens. It will refine the criteria used to select patients for such regimens, decreasing the cost of drug administration in patients who will not benefit from it. Lastly, it will pave the way for future studies showing the potential of repurposing FDA-approved drugs available in off-patent libraries to target ESR regulators and treat early-stage and invasive TNBC cancers, which would reduce the financial investment on drug development, and new clinical trials.