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2012/2013 Cancer stem cells (CSCs) are proposed to be responsible for breast cancer heterogeneity, chemotherapeutic treatment failure, metastatic spread and disease recurrence. The precise identification of the molecular bases that govern the induction and maintenance of CSCs and their aggressive phenotypes is of utmost importance, since it may provide the rational to develop effective therapeutic strategies. In particular there is a considerable effort in finding common pathways, mutations or histological features that might be targeted for therapy, overcoming breast cancer heterogeneity. Here we now demonstrate that CSC self-renewal, chemoresistance, tumour growth and metastases formation capabilities’ are under direct control of Pin1’s enzymatic activity on the Notch signalling pathway. In particular Pin1 protects the nuclear activated forms of Notch1 and Notch4 (N1/4-ICD) from their E3-ubiquitin-ligase Fbxw7α, thereby boosting their protein levels and transcriptional activity. Fbxw7α acts as a potent inhibitor of CSCs maintenance by promoting protein degradation of N1- and N4-ICD, and, as a consequence, this ubiquitin-ligase strongly decreased tumour growth and metastases dissemination in vivo. Interestingly, concomitant over-expression of Pin1 almost completely recovered all these aggressive breast cancer traits. In tissues from breast cancer patients, we observed Notch signalling over-activation despite presence of the negative regulator Fbxw7α, which relied on high Pin1 protein levels. Notably, activation of the Notch-Pin1 axis correlated with poor prognosis in these patients. As a consequence of our findings, suppression of Pin1 holds promise in reverting aggressive phenotypes in breast cancer though shrinkage of CSCs number and a concomitant gain in chemosensitivity, carrying important implications for breast cancers therapy. XXVI Ciclo 1985

Sterol regulatory element binding proteins (SREBPs) are a family of transcription factors that regulate lipid biosynthesis and adipogenesis by controlling the expression of several enzymes required for cholesterol, fatty acid, triacylglycerol and phospholipid synthesis. In vertebrates, SREBP activation is mainly controlled by a complex and well-characterized feedback mechanism mediated by cholesterol, a crucial bio-product of the SREBP-activated mevalonate pathway. In this work, we identified acto-myosin contractility and mechanical forces imposed by the extracellular matrix (ECM) as SREBP1 regulators. SREBP1 control by mechanical cues depends on geranylgeranyl pyrophosphate, another key bio-product of the mevalonate pathway, and impacts on stem cell fate in mouse and on fat storage in Drosophila. Mechanistically, we show that activation of AMP-activated protein kinase (AMPK) by ECM stiffening and geranylgeranylated RhoA-dependent acto-myosin contraction inhibits SREBP1 activation. Our results unveil an unpredicted and evolutionary conserved role of SREBP1 in rewiring cell metabolism in response to mechanical cues., SREBP transcription factors activate lipid synthesis and generate raw materials to lipidate various proteins. Here, the authors show that a stiff cellular environment causes RhoA lipidation and acto-myosin contraction, which inhibits SREBP1 and connects the extracellular matrix to lipid metabolism.

// Cristian Taccioli 1, * , Giovanni Sorrentino 2, 3, * , Alessandro Zannini 2, 3 , Jimmy Caroli 1 , Domenico Beneventano 4 , Laura Anderlucci 5 , Marco Lolli 6 , Silvio Bicciato 1 , Giannino Del Sal 2, 3 1 Department of Life Sciences, University of Modena and Reggio Emilia, Modena 41125, Italy 2 Laboratorio Nazionale CIB (LNCIB), Area Science Park, Trieste 34149, Italy 3 Dipartimento di Scienze della Vita, Universita degli Studi di Trieste, Trieste 34149, Italy 4 Dipartimento di Ingegneria “Enzo Ferrari”, Modena 41125, Italy 5 Dipartimento di Scienze Statistiche, Bologna 40124, Italy 6 Department of Science and Drug Technology, University of Torino, Torino 10125, Italy * These authors have contributed equally to this work Correspondence to: Silvio Bicciato, e-mail: silvio.bicciato@unimore.it Giannino Del Sal, e-mail: delsal@lncib.it Keywords: cancer, targeted therapy, Hippo pathway, small molecules, pharmacogenomics Received: August 10, 2015 Accepted: October 05, 2015 Published: October 15, 2015 ABSTRACT Targeted anticancer therapies represent the most effective pharmacological strategies in terms of clinical responses. In this context, genetic alteration of several oncogenes represents an optimal predictor of response to targeted therapy. Integration of large-scale molecular and pharmacological data from cancer cell lines promises to be effective in the discovery of new genetic markers of drug sensitivity and of clinically relevant anticancer compounds. To define novel pharmacogenomic dependencies in cancer, we created the Mutations and Drugs Portal (MDP, http://mdp.unimore.it ), a web accessible database that combines the cell-based NCI60 screening of more than 50,000 compounds with genomic data extracted from the Cancer Cell Line Encyclopedia and the NCI60 DTP projects. MDP can be queried for drugs active in cancer cell lines carrying mutations in specific cancer genes or for genetic markers associated to sensitivity or resistance to a given compound. As proof of performance, we interrogated MDP to identify both known and novel pharmacogenomics associations and unveiled an unpredicted combination of two FDA-approved compounds, namely statins and Dasatinib, as an effective strategy to potently inhibit YAP/TAZ in cancer cells.

Background The p53 protein family, comprising p53, p63 and p73, is primarily involved in preserving genome integrity and preventing tumor onset, and also affects a range of physiological processes. Signal-dependent modifications of its members and of other pathway components provide cells with a sophisticated code to transduce a variety of stress signaling into appropriate responses. TP53 mutations are highly frequent in cancer and lead to the expression of mutant p53 proteins that are endowed with oncogenic activities and sensitive to stress signaling. Scope of review p53 family proteins have unique structural and functional plasticity, and here we discuss the relevance of prolyl-isomerization to actively shape these features. Major conclusions The anti-proliferative functions of the p53 family are carefully activated upon severe stress and this involves the interaction with prolyl-isomerases. In particular, stress-induced stabilization of p53, activation of its transcriptional control over arrest- and cell death-related target genes and of its mitochondrial apoptotic function, as well as certain p63 and p73 functions, all require phosphorylation of specific S/T-P motifs and their subsequent isomerization by the prolyl-isomerase Pin1. While these functions of p53 counteract tumorigenesis, under some circumstances their activation by prolyl-isomerases may have negative repercussions (e.g. tissue damage induced by anticancer therapies and ischemia-reperfusion, neurodegeneration). Moreover, elevated Pin1 levels in tumor cells may transduce deregulated phosphorylation signaling into activation of mutant p53 oncogenic functions. General significance The complex repertoire of biological outcomes induced by p53 finds mechanistic explanations, at least in part, in the association between prolyl-isomerases and the p53 pathway. This article is part of a Special Issue entitled Proline-directed foldases: Cell signaling catalysts and drug targets.

Mammary epithelial stem cells are fundamental to maintain tissue integrity. Cancer stem cells (CSCs) are implicated in both treatment resistance and disease relapse, and the molecular bases of their malignant properties are still poorly understood. Here we show that both normal stem cells and CSCs of the breast are controlled by the prolyl-isomerase Pin1. Mechanistically, following interaction with Pin1, Notch1 and Notch4, key regulators of cell fate, escape from proteasomal degradation by their major ubiquitin-ligase Fbxw7α. Functionally, we show that Fbxw7α acts as an essential negative regulator of breast CSCs' expansion by restraining Notch activity, but the establishment of a Notch/Pin1 active circuitry opposes this effect, thus promoting breast CSCs self-renewal, tumor growth and metastasis in vivo. In human breast cancers, despite Fbxw7α expression, high levels of Pin1 sustain Notch signaling, which correlates with poor prognosis. Suppression of Pin1 holds promise in reverting aggressive phenotypes, through CSC exhaustion as well as recovered drug sensitivity carrying relevant implications for therapy of breast cancers. © 2013 The Authors., SCOPUS: ar.j, info:eu-repo/semantics/published