The role of SREBP1 in hormone-dependent breast cancer

Despite significant progress in diagnostics and treatments, such as targeted endocrine therapy, 30% of patients with hormone-dependent breast cancer eventually develop disease recurrence predominantly due to drug resistance. Resistance to hormone deprivation therapy is multifactorial and involves several molecular events. An increasing body of research has identified an emerging hallmark of cancer describing the capability of modifying and reprogramming cellular metabolism in order to fuel neoplastic proliferation. Our group has previously uncovered how the specific type of treatment plays a significant role in this process. In particular, breast cancer (BCa) cells developing resistance to aromatase inhibitors (AI) endogenously trigger cholesterol biosynthesis (CB) through sterol regulatory element binding protein 1 (SREBP1) regulation leading to a sustained oestrogen independent, oestrogen receptor alpha (ERα) activation. Cellular lipid metabolism is controlled by SREBP1. The altered lipid metabolism, also known as “lipogenic phenotype”, has been linked with prostate cancer (PCa) pathogenesis: the expression of SREBP1 in prostate cancer is strongly correlated with Gleason grade (pathological grade) and its overexpression is sufficient to increase tumorigenicity and invasion of prostate cancer cells. Furthermore, de novo lipid biosynthesis has been associated with cancer progression, poorer prognosis and shorter patient survival. Considering what is known about the pathobiology of lipids in cancer, it is plausible that invading cells evolve mechanisms to bypass the tight homeostatic regulation of intracellular cholesterol adapting to their new environmental conditions. With this idea in mind, we sought to identify the molecular mechanisms of activation of SREBP1 as key regulator of de novo cholesterol biosynthesis in hormone-dependent cancers resistant to endocrine therapy. Firstly, we wanted to investigate SREBP1 regulation in hormone-dependent cancer cells. We found that SREBP1-driven lipogenesis is consistently upregulated after long-term steroid deprivation, thus when cells become hormone independent. In vivo immunohistochemistry (IHC) data support the hypothesis that SREBP1 might be pivotal in driving de novo cholesterol biosynthesis in endocrine therapy resistant BCa cells. Moreover, the switch of metabolic dependency upon resistance development identified by metabolic profiling, is associated with increased de novo cholesterol and fatty acid synthesis. In order to examine whether cholesterol biosynthesis may be upregulated by modulating SREBP1 signalling, we investigated SREBP1 recruitment to the chromatin. Optimization of ChIP protocol allowed for a genome-wide profiling of SREBP1 binding in BCa and PCa cancer cell lines. Downstream analysis showed a difference in SREBP1 recruitment between parental and long-term starved derived cell lines in MCF7. Furthermore, SREBP1 binding profiles distinguished cancer cells based on the tissue of origin (breast versus prostate cancer). Our data also confirmed a significant co-occurrence between AR and SREBP1 binding sites in PCa and suggested a possible crosstalk between SREBP1 and the ERα in BCa on chromatin. Thirdly, we asked what the targets of SREBP1 are and if they can promote invasive potential. ChIP-seq differential binding analysis unexpectedly revealed non-canonical targets for SREBP1. In particular, we showed that cells acquiring resistance to AI undergo active cytoskeleton re-organisation via Keratin 80 (KRT80) and actin remodelling. This process is driven by epigenetic reprogramming at the type II keratin locus dependent on de novo SREBP1 binding to a single enhancer that is activated upon chronic AI treatment and leading to KRT80 upregulation. Our data strongly suggest that therapy plays a direct role in shaping the biophysical properties and invasive potential of breast cancer cells, by inducing epigenetic rearrangements leading to KRT80 upregulation and concomitant cytoskeletal reorganization. In summary, our study investigates the role of SREBP1 as a key player in endogenous cholesterol accumulation and autonomous activation of the nuclear receptor signalling, leading to the hormone independent tumour proliferation and invasion via global cytoskeletal re-arrangements in hormone-dependent cancers.Open Acces

Impact of COVID-19 on 1-Year Survival Outcomes in Hepatocellular Carcinoma:A Multicenter Cohort Study

IntroductionThe COVID-19 pandemic has caused severe disruption of healthcare services worldwide and interrupted patients' access to essential services. During the first lockdown, many healthcare services were shut to all but emergencies. In this study, we aimed to determine the immediate and long-term indirect impact of COVID-19 health services utilisation on hepatocellular cancer (HCC) outcomes.MethodsA prospective cohort study was conducted from 1 March 2020 until 30 June 2020, correlating to the first wave of the COVID-19 pandemic. Patients were enrolled from tertiary hospitals in the UK and Germany with dedicated HCC management services. All patients with current or past HCC who were discussed at a multidisciplinary meeting (MDM) were identified. Any delay to treatment (DTT) and the effect on survival at one year were reported.ResultsThe median time to receipt of therapy following MDM discussion was 49 days. Patients with Barcelona Clinic Liver Cancer (BCLC) stages-A/B disease were more likely to experience DTT. Significant delays across all treatments for HCC were observed, but delay was most marked for those undergoing curative therapies. Even though severe delays were observed in curative HCC treatments, this did not translate into reduced survival in patients.ConclusionInterruption of routine healthcare services because of the COVID-19 pandemic caused severe delays in HCC treatment. However, DTT did not translate to reduced survival. Longer follow is important given the delay in therapy in those receiving curative therapy

Late cardiotoxicity related to HER2-targeted cancer therapy

Abstract Long-term anti-HER2 therapy in metastatic HER2 + cancers is increasing, but data about the incidence and risk factors for developing late Cancer therapy-related cardiac dysfunction (CTRCD) are missing. We conducted a single-centre, retrospective analysis of a cohort of late anti-HER2 related cardiac dysfunction referred to our Cardio-Oncology service. We include seventeen patients with metastatic disease who developed CTRCD after at least five years of continuous anti-HER2 therapy. Events occurred after a median time of 6.5 years (IQR 5.3-9.0) on anti-HER2 therapy. The lowest (median) LVEF and GLS were 49% (IQR 45–55) and − 15.4% (IQR − 14.9 - -16.3) respectively. All our patients continued or restarted, after a brief interruption, their anti-HER2 therapy. Most (16/17) were started on heart failure medical therapy and normalized their left ventricular ejection fraction at a follow-up. Our study has demonstrated that CTRCD can occur after many years of stability on anti-HER2 therapy and reinforces the importance of continuing cardiovascular surveillance in this population

COVID-19 in breast cancer patients: a subanalysis of the OnCovid registry

Background: cancer patients are at higher risk of COVID-19 complications and mortality than the rest of the population. Breast cancer patients seem to have better prognosis when infected by SARS-CoV-2 than other cancer patients. Methods: we report a subanalysis of the OnCovid study providing more detailed information in the breast cancer population. Results: we included 495 breast cancer patients with a SARS-CoV-2 infection. Mean age was 62.6 years; 31.5% presented more than one comorbidity. The most frequent breast cancer subtype was luminal-like (n = 245, 49.5%) and 177 (35.8%) had metastatic disease. A total of 332 (67.1%) patients were receiving active treatment, with radical intent in 232 (47.6%) of them. Hospitalization rate was 58.2% and all-cause mortality rate was 20.3%. One hundred twenty-nine (26.1%) patients developed one COVID-19 complication, being acute respiratory failure the most common (n = 74, 15.0%). In the multivariable analysis, age older than 70 years, presence of COVID-19 complications, and metastatic disease were factors correlated with worse outcomes, while ongoing anticancer therapy at time of COVID-19 diagnosis appeared to be a protective factor. No particular oncological treatment was related to higher risk of complications. In the context of SARS-CoV-2 infection, 73 (18.3%) patients had some kind of modification on their oncologic treatment. At the first oncological reassessment (median time: 46.9 days ± 36.7), 255 (51.6%) patients reported to be fully recovered from the infection. There were 39 patients (7.9%) with long-term SARS-CoV-2-related complications. Conclusion: in the context of COVID-19, our data confirm that breast cancer patients appear to have lower complications and mortality rate than expected in other cancer populations. Most breast cancer patients can be safely treated for their neoplasm during SARS-CoV-2 pandemic. Oncological treatment has no impact on the risk of SARS-CoV-2 complications, and, especially in the curative setting, the treatment should be modified as little as possible

The Systemic Inflammatory Response Identifies Patients with Adverse Clinical Outcome from Immunotherapy in Hepatocellular Carcinoma

Systemic inflammation is a hallmark of cancer, and it has a pivotal role in hepatocellular carcinoma (HCC) development and progression. We conducted a retrospective study including 362 patients receiving immune check-point inhibitors (ICIs) across three continents, evaluating the influence of neutrophiles to lymphocytes ratio (NLR), platelets to lymphocytes ratio (PLR), and prognostic nutritional index (PNI) on overall (OS), progression free survival (PFS), and radiologic responses. In our 362 patients treated with immunotherapy, median OS and PFS were 9 and 3.5 months, respectively. Amongst tested inflammatory biomarkers, patients with NLR ≥ 5 had shorter OS (7.7 vs. 17.6 months, p < 0.0001), PFS (2.1 vs. 3.8 months, p = 0.025), and lower objective response rate (ORR) (12% vs. 22%, p = 0.034); similarly, patients with PLR ≥ 300 reported shorter OS (6.4 vs. 16.5 months, p < 0.0001) and PFS (1.8 vs. 3.7 months, p = 0.0006). NLR emerged as independent prognostic factors for OS in univariate and multivariate analysis (HR 1.95, 95%CI 1.45–2.64, p < 0.001; HR 1.73, 95%CI 1.23–2.42, p = 0.002) and PLR remained an independent prognostic factor for both OS and PFS in multivariate analysis (HR 1.60, 95%CI 1.6–2.40, p = 0.020; HR 1.99, 95%CI 1.11–3.49, p = 0.021). Systemic inflammation measured by NLR and PLR is an independent negative prognostic factor in HCC patients undergoing ICI therapy. Further studies are required to understand the biological mechanisms underlying this association and to investigate the predictive significance of circulating inflammatory biomarkers in HCC patients treated with ICIs

Acquired CYP19A1 amplification is an early specific mechanism of aromatase inhibitor resistance in ERα metastatic breast cancer

Tumor evolution is shaped by many variables, potentially involving external selective pressures induced by therapies. After surgery, patients with estrogen receptor (ERα)-positive breast cancer are treated with adjuvant endocrine therapy, including selective estrogen receptor modulators (SERMs) and/or aromatase inhibitors (AIs). However, more than 20% of patients relapse within 10 years and eventually progress to incurable metastatic disease. Here we demonstrate that the choice of therapy has a fundamental influence on the genetic landscape of relapsed diseases. We found that 21.5% of AI-treated, relapsed patients had acquired CYP19A1 (encoding aromatase) amplification (CYP19A1(amp)). Relapsed patients also developed numerous mutations targeting key breast cancer-associated genes, including ESR1 and CYP19A1. Notably, CYP19A1(amp) cells also emerged in vitro, but only in AI-resistant models. CYP19A1 amplification caused increased aromatase activity and estrogen-independent ERα binding to target genes, resulting in CYP19A1(amp) cells showing decreased sensitivity to AI treatment. These data suggest that AI treatment itself selects for acquired CYP19A1(amp) and promotes local autocrine estrogen signaling in AI-resistant metastatic patients