BACKGROUND: Recent studies have suggested that fatty acid oxidation (FAO) is a key metabolic pathway for the growth of triple negative breast cancers (TNBCs), particularly those that have high expression of MYC. However, the underlying mechanism by which MYC promotes FAO remains poorly understood. METHODS: We used a combination of metabolomics, transcriptomics, bioinformatics, and microscopy to elucidate a potential mechanism by which MYC regulates FAO in TNBC. RESULTS: We propose that MYC induces a multigenic program that involves changes in intracellular calcium signalling and fatty acid metabolism. We determined key roles for fatty acid transporters (CD36), lipases (LPL), and kinases (PDGFRB, CAMKK2, and AMPK) that each contribute to promoting FAO in human mammary epithelial cells that express oncogenic levels of MYC. Bioinformatic analysis further showed that this multigenic program is highly expressed and predicts poor survival in the claudin-low molecular subtype of TNBC, but not other subtypes of TNBCs, suggesting that efforts to target FAO in the clinic may best serve claudin-low TNBC patients. CONCLUSION: We identified critical pieces of the FAO machinery that have the potential to be targeted for improved treatment of patients with TNBC, especially the claudin-low molecular subtype.
Epidermolysis bullosa (EB) is a heterogeneous group of rare, inherited genodermatoses characterized by skin and mucosal fragility with chronic blistering from minor trauma. 1 Patients with EB are more susceptible to developing squamous cell carcinoma (SCC) at mucocutaneous sites of chronic inflammation and fibrosis. 2 SCC is a major cause of mortality in patients with recessive dystrophic EB (RDEB), with a 90% risk of developing SCC by age 55. 3,4 While advances in gene replacement therapy at affected sites offer promise for some EB patients, the mainstay of treatment for SCC remains supportive care and surveillance. 5,6 EB-associated SCC is managed with wide local excision and amputation of highly affected limbs, as there are few effective chemotherapeutic options for advanced or metastatic SCC. 7 Triterpenoids are a class of compounds derived from plants that inhibit the pro-inflammatory nuclear factor-kB (NF-kB) pathway and modulate inflammatory mediators such as iNOS, 5-LOX and COX-2. 8 RTA 408 (Omaveloxolone) is a synthetic compound derived from triterpenoid CDDO-Me, both of which have been shown to activate the antioxidative transcription factor Nrf2 to reduce oxidative damage and inflammation. 9,10 CDDO-Me and RTA 408 have previously been shown to inhibit growth in human breast, lung and prostate cancer in several preclinical studies. 11-14 However, whether these compounds are effective in treating SCC has not been investigated.RTA 408 is currently in a clinical trial as a treatment of Friedreich Ataxia for its antioxidant and anti-inflammatory action. 15 Because RTA 408 dually inhibits inflammation and tumour growth, we investigated its effectiveness on chronic inflammation in EB and SCC tumour growth. Here, we report the effects of RTA 408 treatment
Patients with HER2-positive breast cancer have seen improved survival and outcomes over the past two decades. As patients live longer, the incidence of CNS metastases has increased in this population. The authors’ review outlines the most current data in HER2-positive brain and leptomeningeal metastases and discuss the current treatment paradigm in this disease. Up to 55% of HER2-positive breast cancer patients go on to experience CNS metastases. They may present with a variety of focal neurologic symptoms, such as speech changes or weakness, and may also have more diffuse symptoms related to high intracranial pressure, such as headaches, nausea, or vomiting. Treatment can include focal treatments, such as surgical resection or radiation (focal or whole-brain radiation), as well as systemic therapy options or even intrathecal therapy in the case of leptomeningeal disease. There have been multiple advancements in systemic therapy for these patients over the past few years, including the availability of tucatinib and trastuzumab-deruxtecan. Hope remains high as clinical trials for CNS metastases receive greater attention and as other HER2-directed methods are being studied in clinical trials with the goal of better outcomes for these patients.
MYC is one of the most commonly mutated and highly amplified oncogenes in human breast cancer. MYC amplifications occur most frequently in triple-negative breast cancers (TNBCs). TNBCs can be divided into two molecular subtypes: basal-like and claudin-low breast cancers. These cancers tend to be extremely aggressive and are strongly associated with disease recurrence, poor prognosis and high mortality. In particular, claudin-low tumors are classified by a loss of tight junctions and cell-tocell contacts and an enrichment for genes associated with an epithelial-to-mesenchymal transition (EMT) and mammary stem cells (also known as tumor-initiating cells). Despite the high level of disease severity, there are no targeted therapies for claudin-low TNBCs. To address this unmet need, we utilized human mammary epithelial cells (HuMECs) that express oncogenic levels of MYC and a mutant MYC (T58A) to characterize the behavioral and metabolic changes that occur during the formation of MYC-driven breast cancers. We found that MYC regulates the expression of genes associated with cell stemness, EMT, lipid metabolism, and calcium (Ca2+) signaling and that the expression of this gene signature promotes cell growth, survival, migration, and metabolic plasticity. The gene signature of MYC-expressing HuMECs highly correlates with the gene signature of claudinlow breast cancers, therefore highlighting the relevance of our HuMEC model to human claudin-low breast cancer. We found the major drivers underlying the MYC-dependent changes in cell behavior to be stimulation of Ca2+ signaling and strong activation of lipid metabolism. Ca2+ signaling is stimulated through the MYC-dependent repression of Ca2+ efflux mechanisms; elevated cytosolic Ca2+ then consequently stimulates a Ca2+/calmodulin kinase kinase 2 (CAMKK2)/AMPK signaling axis that activates fatty acid scavenging and transport, as well as β-oxidation. Enhanced lipid metabolism thereby provides the necessary biomass (fatty acids) for phospholipid biosynthesis and energy (ATP) to support the metabolically demanding processes of cell growth, proliferation, and migration. In all, our findings provide a strong rationale for targeting lipid metabolism and the Ca2+/CAMKK2/AMPK signaling axis in MYC-driven, and potentially claudin-low, breast cancers.
The patched tumor suppressor gene (PTCH1) encodes a receptor, which is a key component of the hedgehog signalling pathway. Mutations in PTCH1 are implicated in the development of sporadic basal cell carcinomas (BCC), as well as those in Gorlin Syndrome. Rarely, BCCs may develop in a linear pattern along lines of Blaschko due to cutaneous mosaicism. In cases in which there are other features of Gorlin syndrome, genomic analysis has demonstrated lesional mutations in the Hedgehog signalling pathway. Causative mutations, however, have not been firmly demonstrated in the cases of linear and segmental BCCs in otherwise healthy individuals. Herein, we report a case of a 31 year‐old Caucasian woman with linear development of multiple superficial BCCs in a Blaschkoid distribution without other characteristic findings of Gorlin syndrome. Genomic analysis of lesional skin by whole‐exome sequencing identified a novel heterozygous mutation PTCH1: NM_000264.3, Exon 15, c.2336‐2337insGGTAGGA, p.Asp779Glufs*13 in PTCH1, shared by two discrete samples within the lesion, while no mutations were found in the non‐lesional skin or peripheral blood. Given the young age of our patient and linear distribution of BCCs on non‐sun exposed skin, our findings suggest segmental mosaicism. The patient was treated with topical 5% imiquimod with histologically confirmed clearance of BCCs in 2 months.
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