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Although human epidermal growth factor receptor 2 (HER2)-targeted therapies have dramatically improved the clinical outcome of HER2-positive breast cancer patients, innate and acquired resistance remains an important clinical challenge. New therapeutic approaches and diagnostic tools for identification, stratification, and treatment of patients at higher risk of resistance and recurrence are therefore warranted. Here, we unveil a mechanism controlling the oncogenic activity of HER2: heteromerization with the cannabinoid receptor CB2R. We show that HER2 physically interacts with CB2R in breast cancer cells, and that the expression of these heteromers correlates with poor patient prognosis. The cannabinoid Δ9-tetrahydrocannabinol (THC) disrupts HER2–CB2R complexes by selectively binding to CB2R, which leads to (i) the inactivation of HER2 through disruption of HER2–HER2 homodimers, and (ii) the subsequent degradation of HER2 by the proteasome via the E3 ligase c-CBL. This in turn triggers antitumor responses in vitro and in vivo. Selective targeting of CB2R transmembrane region 5 mimicked THC effects. Together, these findings define HER2–CB2R heteromers as new potential targets for antitumor therapies and biomarkers with prognostic value in HER2-positive breast cancer.

Background Transglycosylation represents one of the most promising approaches for obtaining novel glycosides, and plant phenols and polyphenols are emerging as one of the best targets for creating new molecules with enhanced capacities. These compounds can be found in diet and exhibit a wide range of bioactivities, such as antioxidant, antihypertensive, antitumor, neuroprotective and anti-inflammatory, and the eco-friendly synthesis of glycosides from these molecules can be a suitable alternative for increasing their health benefits. Results Transglycosylation experiments were carried out using different GH3 β-glucosidases from the fungus Talaromyces amestolkiae . After a first screening with a wide variety of potential transglycosylation acceptors, mono-glucosylated derivatives of hydroxytyrosol, vanillin alcohol, 4-hydroxybenzyl alcohol, and hydroquinone were detected. The reaction products were analyzed by thin-layer chromatography, high-pressure liquid chromatography, and mass spectrometry. Hydroxytyrosol and vanillyl alcohol were selected as the best options for transglycosylation optimization, with a final conversion yield of 13.8 and 19% of hydroxytyrosol and vanillin glucosides, respectively. NMR analysis confirmed the structures of these compounds. The evaluation of the biological effect of these glucosides using models of breast cancer cells, showed an enhancement in the anti-proliferative capacity of the vanillin derivative, and an improved safety profile of both glucosides. Conclusions GH3 β-glucosidases from T. amestolkiae expressed in P. pastoris were able to transglycosylate a wide variety of acceptors. Between them, phenolic molecules like hydroxytyrosol, vanillin alcohol, 4-hydroxybenzyl alcohol, and hydroquinone were the most suitable for its interesting biological properties. The glycosides of hydroxytyrosol and vanillin were tested, and they improved the biological activities of the original aglycons on breast cancer cells. Electronic supplementary material The online version of this article (10.1186/s12934-019-1147-4) contains supplementary material, which is available to authorized users.

Metastases's spreading is the main cause of mortality for advanced stage cancer patients, including melanoma. The formation of metastases is favored by enhanced migratory and invasive capacities of tumor cells. Tumor suppressor gene NF1 is a negative regulator of RAS and its deregulation plays an important role in several aspects of melanoma transformation and progression. However, very little is described about the role of NF1 in cellular migration and invasion. In this study, our results show on the one hand, that the loss of NF1 expression delays migration of human melanoblasts via a RAC1-dependent mechanism. On the other hand, our data indicate that NF1 loss in melanoma cells is enhancing migration, intravasation and metastases formation in vivo . Moreover, not only this phenotype is associated with an upregulation of PREX1 but also patient-derived melanoma samples with low NF1 expression present increased levels of PREX1. In sum, our study brings new elements on the mechanism controlling cellular migration in the context of NF1 loss. These data are of prime interest to improve treatment strategies against all NF1 -mutated tumors, including this subtype of melanoma.

Mammary gland development occurs primarily in the adult, undergoing extensive expansion during puberty followed by cycles of functional specialization and regression with every round of pregnancy/lactation/involution. This process is ultimately driven by the coordinated proliferation and differentiation of mammary epithelial cells, but the endogenous factors regulating these developmental dynamics are still poorly defined. Endocannabinoid signaling is known to determine cell fate-related events involved in the development of different organs in the central nervous system and the periphery. Here, we report that the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) plays a pivotal role in adult mammary gland development. Specifically, it is required for luminal lineage specification in the mammary gland, and it promotes hormone-driven secretory differentiation of mammary epithelial cells by controlling the endogenous levels of anandamide and the subsequent activation of CB1R. Together, our results shed some light on the role of the endocannabinoid system in breast development and introduce FAAH-signaling as a new therapeutic target in milk production deficits.

Introduction There are three major stages of breast development -embryonic, pubertal, and reproductive. During this complex developmental cycling, the epithelial compartment undergoes several rounds of proliferation, remodelling and cell death to eventually form an organised and functional mammary tree. The very nature of the pathways controlling these processes makes them susceptible to promote tumorigenic processes and ultimately lead to breast carcinoma.Fatty acid amide hydrolase (FAAH) is an integral membrane enzyme that hydrolyzes the endocannabinoid anandamide and related amidated signalling lipids. Here, we aimed at analysing the expression FAAH in breast physio-pathology. Material and methods The expression of FAAH was analysed by immunohistochemistry in a tissue microarray (TMA) containing »600 human breast cancer samples and in public microarrays data bases. Cell lines derived from different breast cancer subtypes have been analysed for FAAH expression and the effect of a Knock-out (CRISPR) and overexpression of FAAH examined. FACS and immunofluorescence were also performed to further assess the identity of cell populations. FAAH effects on breast CSC activity was examinated using mammosphere formation and aldehyde dehydrogenase (ALDH) activity assays. Results and discussionsWe have found that FAAH shows remarkable variations in expression within the human breast epithelial hierarchy. Particularly, FAAH expression is restricted to a certain subset of mature cells in normal breast tissue (i.e. luminal cells), with negligible levels being detected in the progenitor/stem cell subset, In line with this idea, pharmacological inhibition of FAAH with URB597 in the mammary stem cell line HC11 delayed differentiation to mature epithelial cells. In addition, we observed significant differences in duct formation between FAAH KO and WT mice during pubertal development.Our results also correlate low FAAH expression with more undifferentiated phenotypes, high histologic grade, absence of oestrogen receptor and triple-negative phenotype in breast cancer. Consistent with this, we found low FAAH mRNA levels associated with metastasis and poor prognosis gene signatures. Finally, pharmacoinhibition and knocking-out of FAAH in breast cancer lines, enriched the cultures in cancer stem cells. Conclusion Together, our data suggest that FAAH plays a role in breast cell differentiation, both in normal development and in oncologic contexts. Introduction Glioblastoma (GBM) is the most aggressive primary brain tumour. Treatment failure and recurrence are explained by intratumoral heterogeneity. Our previous results showed that the integrin a5b1, the fibronectin receptor, is implicated in GBM aggressiveness and represents a pertinent therapeutic target. Recently, we observed that its expression was heterogeneous between patient tumours but also between different areas in a given tumour. We hypothesised that this intratumoral heterogeneity may be linked to different glioma initiating cells (GIC). Material and methods GICs were grow...

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