A multifactorial \u2018Consensus Signature\u2019 by in silico analysis to predict response to neoadjuvant anthracycline-based chemotherapy in triple-negative breast cancer

BACKGROUND: Owing to the complex processes required for anthracycline-induced cytotoxicity, a prospectively defined multifactorial Consensus Signature (ConSig) might improve prediction of anthracycline response in triple-negative breast cancer (TNBC) patients, whose only standard systemic treatment option is chemotherapy. AIMS: We aimed to construct and evaluate a multifactorial signature, comprising measures of each function required for anthracycline sensitivity in TNBC. METHODS: ConSigs were constructed based on five steps required for anthracycline function: drug penetration, nuclear topoisomerase II\u3b1 (topoII\u3b1) protein location, increased topoII\u3b1 messenger RNA (mRNA) expression, apoptosis induction, and immune activation measured by, respectively, HIF1\u3b1 or SHARP1 signature, LAPTM4B mRNA, topoII\u3b1 mRNA, Minimal Gene signature or YWHAZ mRNA, and STAT1 signature. TNBC patients treated with neoadjuvant anthracycline-based chemotherapy without taxane were identified from publicly available gene expression data derived with Affymetrix HG-U133 arrays (training set). In silico analyses of correlation between gene expression data and pathological complete response (pCR) were performed using receiver-operating characteristic curves. To determine anthracycline specificity, ConSigs were assessed in patients treated with anthracycline plus taxane. Specificity, sensitivity, positive and negative predictive value, and odds ratio (OR) were calculated for ConSigs. Analyses were repeated in two validation gene expression data sets derived using different microarray platforms. RESULTS: In the training set, 29 of 147 patients had pCR after anthracycline-based chemotherapy. Various combinations of components were evaluated, with the most powerful anthracycline response predictors being ConSig1: (STAT1+topoII\u3b1 mRNA +LAPTM4B) and ConSig2: (STAT1+topoII\u3b1 mRNA+HIF1\u3b1). ConSig1 demonstrated high negative predictive value (85%) and high OR for no pCR (3.18) and outperformed ConSig2 in validation sets for anthracycline specificity. CONCLUSIONS: With further validation, ConSig1 may help refine selection of TNBC patients for anthracycline chemotherapy

Urinary estrogen metabolites and prostate cancer : a case-control study and meta-analysis

Objective: To investigate prostate cancer (Pca) risk in relation to estrogen metabolism, expressed as urinary 2-hydroxyestrone (2-OHE1), 16α-hydroxyestrone (16α-OHE1) and 2-OHE1 to 16α-OHE1 ratio. Methods: We conducted a case-control study within the Western New York Health Cohort Study (WNYHCS) from 1996 to 2001. From January 2003 through September 2004, we completed the re-call and follow-up of 1092 cohort participants. Cases (n = 26) and controls (n = 110) were matched on age, race and recruitment period according to a 1:4 ratio. We used the unconditional logistic regression to compute crude and adjusted odds ratios (OR) and 95% confident interval (CI) of Pca in relation to 2-OHE1, 16αOHE1 and 2-OHE1 to 16α-OHE1 by tertiles of urine concentrations (stored in a biorepository for an average of 4 years). We identified age, race, education and body mass index as covariates. We also conducted a systematic review of the literature which revealed no additional studies, but we pooled the results from this study with those from a previously conducted case-control study using the DerSimonian-Laird random effects method. Results: We observed a non-significant risk reduction in the highest tertile of 2-OHE1 (OR 0.72, 95% CI 0.25-2.10). Conversely, the odds in the highest tertile of 16α-OHE1 showed a non-significant risk increase (OR 1.76 95% CI 0.62-4.98). There was a suggestion of reduced Pca risk for men in the highest tertile of 2-OHE1 to 16α-OHE1 ratio (OR 0.56, 95% CI 0.19-1.68). The pooled estimates confirmed the association between an increased Pca risk and higher urinary levels of 16α-OHE1 (third vs. first tertile: OR 1.82, 95% CI 1.09-3.05) and the protective effect of a higher 2-OHE 1 to 16α-OHE1 ratio (third vs. first tertile: OR 0.53, 95% CI 0.31-0.90). Conclusion: Our study and the pooled results provide evidence for a differential role of the estrogen hydroxylation pathway in Pca development and encourage further study

Charting differentially methylated regions in cancer with Rocker-meth

Matteo Benelli et al. present Rocker-meth, a new Hidden Markov Model (HMM)-based method, to robustly identify differentially methylated regions (DMRs). They use Rocker-meth to analyse more than 6000 methylation profiles across 14 cancer types, providing a catalog of tumor-specific and shared DMRs

Mitochondrial fission and cristae disruption increase the response of cell models of Huntington's disease to apoptotic stimuli

Huntington's disease (HD), a genetic neurodegenerative disease caused by a polyglutamine expansion in the Huntingtin (Htt) protein, is accompanied by multiple mitochondrial alterations. Here, we show that mitochondrial fragmentation and cristae alterations characterize cellular models of HD and participate in their increased susceptibility to apoptosis. In HD cells, the increased basal activity of the phosphatase calcineurin dephosphorylates the pro-fission dynamin related protein 1 (Drp1), increasing its mitochondrial translocation and activation, and ultimately leading to fragmentation of the organelle. The fragmented HD mitochondria are characterized by cristae alterations that are aggravated by apoptotic stimulation. A genetic analysis indicates that correction of mitochondrial elongation is not sufficient to rescue the increased cytochrome c release and cell death observed in HD cells. Conversely, the increased apoptosis can be corrected by manoeuvres that prevent fission and cristae remodelling. In conclusion, the cristae remodelling of the fragmented HD mitochondria contributes to their hypersensitivity to apoptosis

Glucose Metabolic Reprogramming of ER Breast Cancer in Acquired Resistance to the CDK4/6 Inhibitor Palbociclib

The majority of breast cancers express the estrogen receptor (ER) and are dependent on estrogen for their growth and survival. Endocrine therapy (ET) is the standard of care for these tumors. However, a superior outcome is achieved in a subset of ER positive (ER+)/human epidermal growth factor receptor 2 negative (HER2−) metastatic breast cancer patients when ET is administrated in combination with a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor, such as palbociclib. Moreover, CDK4/6 inhibitors are currently being tested in ER+/HER2+ breast cancer and reported encouraging results. Despite the clinical advances of a combinatorial therapy using ET plus CDK4/6 inhibitors, potential limitations (i.e., resistance) could emerge and the metabolic adaptations underlying such resistance warrant further elucidation. Here we investigate the glucose-dependent catabolism in a series of isogenic ER+ breast cancer cell lines sensitive to palbociclib and in their derivatives with acquired resistance to the drug. Importantly, ER+/HER2− and ER+/HER2+ cell lines show a different degree of glucose dependency. While ER+/HER2− breast cancer cells are characterized by enhanced aerobic glycolysis at the time of palbociclib sensitivity, ER+/HER2+ cells enhance their glycolytic catabolism at resistance. This metabolic phenotype was shown to have prognostic value and was targeted with multiple approaches offering a series of potential scenarios that could be of clinical relevance

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field

Breast cancer endocrine resistance: stress-related kinase pathways and the role of JNK/AP-1

Background: Endocrine treatment is the mainstay therapy for estrogen receptor positive (ER+) breast cancer patients. Although effective in many cases, some patients do not respond to endocrine therapy and display de novo resistance, while a substantial fraction of initially responding patients ultimately acquires resistance. Understanding the complex biology underlying resistance is critical for the development of new therapeutic strategies for these patients. Methods and results: We performed expression array analysis of xenograft tumors from two well characterized models of endocrine resistance that recapitulate relevant clinical scenarios: MCF7, and its HER2 overexpressing derivative model, MCF7/HER2-18. We developed gene classifiers representing differentially regulated transcripts at the time of resistance and analyzed them using publicly available datasets from breast cancer cell lines and breast cancer patients. We found that resistant tumors undergo complex phenotypic changes at time of resistance. Resistant tumors showed upregulation of a set of genes that is overexpressed in ER-/HER2+ human tumors, and showed downregulation of classical ER-dependent genes. Therefore, at time of resistance, ER signaling appears to be effectively impaired by endocrine treatment while alternative pathways are activated, sustaining endocrine resistant growth. Evidence from the expression array data and from other studies in our group suggests that the stress-related kinase pathways JNK/AP-1 and p38 MAPK are activated at time of resistance. Therefore, we studied these pathways in greater detail. To investigate the role of JNK/AP-1 inhibition, we used MCF7 cells stably transfected with an inducible, dominant negative (DN) cJun. Two clones were studied in vitro and grown as xenografts in mice treated with endocrine therapy, either in the presence or absence of DN cJun. Expression of DN cJun in both clones potentiated the effect of endocrine treatment both in vitro and in vivo. We observed that endocrine treatment induces mainly a cytostatic effect when used on its own, but elicits dramatic cytotoxicity when used concomitantly with AP-1 blockade. Tumors treated with endocrine therapy in combination with AP-1 inhibition responded significantly faster to treatment compared to control tumors. When the DN cJun was induced at time of endocrine resistance, we observed striking tumor response in all tumors, suggesting that AP-1 blockade can effectively reverse the resistant phenotype. To investigate the role of p38MAPK, we generated MCF7 clones stably expressing DN p38 in an inducible fashion. After validating the effectiveness of p38 pathway blockade in the clones, we studied the effect of such inhibition in combination with endocrine treatment. In vivo data from DNp38 xenografts suggest that p38 inhibition reduces tumor growth rate when tumors start to develop resistance, while surprisingly accelerating tumor growth in endocrine naïve tumors. Conclusions: Our data show that, when challenged with endocrine therapy, over time the molecular phenotypes of breast cancer may change, and that resistant tumors may rely on new, alternative escape pathways. We, for the first time, provide proof that stress-related kinase pathways such as JNK/AP-1 and p38 may participate in such alternative resistance mechanisms. Therefore, these pathways are promising therapeutic targets for endocrine resistant breast cancer. Further preclinical, as well as clinical, studies are warranted

Managing advanced HR-positive, HER2-negative breast cancer with CDK4/6 inhibitors in post-menopausal patients: is there a best sequence?

The current therapeutic landscape of luminal human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (mBC) is fundamentally evolving, particularly in the advent of molecularly targeted therapies, such as inhibitors of mammalian target of rapamycin and cyclin-dependent kinase 4/6 (CDK4/6). In the context of CDK4/6 inhibitors, landmark clinical trials for palbociclib (PALOMA-1, PALOMA-2, PALOMA-3), ribociclib (MONALEESA-2, MONALEESA-3, MONALEESA-7) and abemaciclib (MONARCH-1, MONARCH-2, MONARCH-3) have provided solid data regarding progression-free survival and overall response rate, justifying the introduction of this class of drugs into our therapeutic armoury. However, several clinical questions remain open. One of the most relevant issues faced in practice is that of the optimum sequencing of CDK4/6 inhibitors, particularly given the wide range of therapeutic options open to clinicians treating luminal mBC. In this brief commentary, we would like to focus on the best sequence for CDK4/6 inhibitors and their place in this growing, complex scenario