Triple-negative breast cancer (TNBC) has limited therapeutic options, is highly metastatic and characterized by early recurrence. Lipid metabolism is generally deregulated in TNBC and might reveal vul Show more
Triple-negative breast cancer (TNBC) has limited therapeutic options, is highly metastatic and characterized by early recurrence. Lipid metabolism is generally deregulated in TNBC and might reveal vulnerabilities to be targeted or used as biomarkers with clinical value. Ferroptosis is a type of cell death caused by iron-dependent lipid peroxidation which is facilitated by the presence of polyunsaturated fatty acids (PUFA). Here we identify fatty acid desaturases 1 and 2 (FADS1/2), which are responsible for PUFA biosynthesis, to be highly expressed in a subset of TNBC with a poorer prognosis. Lipidomic analysis, coupled with functional metabolic assays, showed that FADS1/2 high-expressing TNBC are susceptible to ferroptosis-inducing agents and that targeting FADS1/2 by both genetic interference and pharmacological approach renders those tumors ferroptosis-resistant while unbalancing PUFA/MUFA ratio by the supplementation of exogenous PUFA sensitizes resistant tumors to ferroptosis induction. Last, inhibiting lipid droplet (LD) formation and turnover suppresses the buffering capacity of LD and potentiates iron-dependent cell death. These findings have been validated in vitro and in vivo in mouse- and human-derived clinically relevant models and in a retrospective cohort of TNBC patients. Show less
Arrhythmogenic cardiomyopathy (ACM) and hypertrophic cardiomyopathy (HCM) are genetically and phenotypically distinct disorders of the myocardium. Here we describe for the first time co-inheritance of Show more
Arrhythmogenic cardiomyopathy (ACM) and hypertrophic cardiomyopathy (HCM) are genetically and phenotypically distinct disorders of the myocardium. Here we describe for the first time co-inheritance of mutations in genes associated with ACM or HCM in two families with recurrence of both cardiomyopathies. Among the double heterozygotes for mutations in desmoplakin (DSP) and myosin binding protein C (MYBPC3) genes identified in Family A, two were diagnosed with ACM and two with HCM. In Family B, one patient was identified to carry mutations in α-T-catenin (CTTNA3) and β-myosin (MYH7) genes, but he does not fulfill the current diagnostic criteria neither for ACM nor for HCM. Interestingly, the double heterozygotes showed a variable clinical expression of both cardiomyopathies and they do not exhibit a more severe phenotype than family members carrying only one of the two mutations. Show less