Cancer immunotherapy has been heralded as a breakthrough cancer treatment demonstrating tremendous success in improving tumor responses and survival of patients with hematological cancers and solid tumors. This novel promising treatment approach has in particular triggered optimism for triple negative breast cancer (TNBC) treatment, a subtype of breast cancer with distinct clinical features and poor clinical outcome. In early 2019, the FDA granted the first approval of immune checkpoint therapy, targeting PD-L1 (Atezolizumab) in combination with chemotherapy for the treatment of patients with locally advanced or metastatic PD-L1 positive TNBC. The efficacy of immuno-based interventions varies across cancer types and patient cohorts, which is attributed to a variety of lifestyle, clinical, and pathological factors. For instance, obesity has emerged as a risk factor for a dampened anti-tumor immune response and increased risk of immunotherapy-induced immune-related adverse events (irAEs) but has also been linked to improved outcomes with checkpoint blockade. Given the breadth of the rising global obesity epidemic, it is imperative to gain insight into the immunomodulatory effects of obesity in the peripheral circulation and within the tumor microenvironment. In this review, we resolve the impact of obesity on breast tumorigenesis and progression on the one hand, and on the immune contexture on the other hand. Finally, we speculate on the potential implications of obesity on immunotherapy response in breast cancer. This review clearly highlights the need for in vivo obese cancer models and representative clinical cohorts for evaluation of immunotherapy efficacy.

Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, is a complex multifactorial disease characterized by metabolic deregulations that include accumulation of lipids in the liver, lipotoxicity, and insulin resistance. The progression of NAFLD to non-alcoholic steatohepatitis and cirrhosis, and ultimately to carcinomas, is governed by interplay of pro-inflammatory pathways, oxidative stress, as well as fibrogenic and apoptotic cues. As the liver is the major organ of biotransformation, deregulations in hepatic signaling pathways have effects on both, xenobiotic and endobiotic metabolism. Several major nuclear receptors involved in the transcription and regulation of phase I and II drug metabolizing enzymes and transporters also have endobiotic ligands including several lipids. Hence, hepatic lipid accumulation in steatosis and NAFLD, which leads to deregulated activation patterns of nuclear receptors, may result in altered drug metabolism capacity in NAFLD patients. On the other hand, genetic and association studies have indicated that a malfunction in drug metabolism can affect the prevalence and severity of NAFLD. This review focuses on the complex interplay between NAFLD pathogenesis and drug metabolism. A better understanding of these relationships is a prerequisite for developing improved drug dosing algorithms for the pharmacotherapy of patients with different stages of NAFLD.

The triple negative breast cancer (TNBC) paradox marks a major challenge in the treatment-decision making process. TNBC patients generally respond better to neoadjuvant chemotherapy compared to other breast cancer patients; however, they have a substantial higher risk of disease recurrence. We evaluated the expression of the tumor-associated antigen PReferentially Antigen expressed in MElanoma (PRAME) as a prognostic biomarker in breast cancer and explored its role in cell migration and invasion, key hallmarks of progressive and metastatic disease. TCGA and GTeX datasets were interrogated to assess the expression of PRAME in relation to overall and disease-free survival. The role of PRAME in cell migration and invasion was investigated using gain- and loss-of-function TNBC cell line models. We show that PRAME promotes migration and invasion of TNBC cells through changes in expression of E-cadherin, N-cadherin, vimentin and ZEB1, core markers of an epithelial-to-mesenchymal transition. Mechanistic analysis of PRAME-overexpressing cells showed an upregulation of 11 genes (SNAI1, TCF4, TWIST1, FOXC2, IL1RN, MMP2, SOX10, WNT11, MMP3, PDGFRB, and JAG1) and downregulation of 2 genes (BMP7 and TSPAN13). Gene ontology analyses revealed enrichment of genes that are dysregulated in ovarian and esophageal cancer and are involved in transcription and apoptosis. In line with this, interrogation of TCGA and GTEx data demonstrated an increased PRAME expression in ovarian and esophageal tumor tissues in addition to breast tumors where it is associated with worse survival. Our findings indicate that PRAME plays a tumor-promoting role in triple negative breast cancer by increasing cancer cell motility through EMT-gene reprogramming. Therefore, PRAME could serve as a prognostic biomarker and/or therapeutic target in TNBC.

Neuropilin-1 (NRP-1), a non-tyrosine kinase glycoprotein receptor, is associated with poor prognosis breast cancer, however transcriptomic changes triggered by NRP-1 overexpression and its association with chemoresistance in breast cancer have not yet been explored. BT-474 NRP-1 variant cells were generated by stable overexpression of NRP-1 in the BT-474 breast cancer cell line. RNA sequencing and qRT-PCR were conducted to identify differentially expressed genes. The role of an upregulated oncogene, Tenascin C (TNC) and its associated pathway was investigated by siRNA-mediated knockdown. Resistant variants of the control and BT-474 NRP-1 cells were generated by sequential treatment with four cycles of Adriamycin/Cyclophosphamide (4xAC) followed by four cycles of Paclitaxel (4xAC + 4xPAC). NRP-1 overexpression increased cellular tumorigenic behavior. RNA sequencing identified upregulation of an oncogene, Tenascin-C (TNC) and downregulation of several tumor suppressors in BT-474 NRP-1 cells. Additionally, protein analysis indicated activation of the TNC-associated integrin β3 (ITGB3) pathway via focal adhesion kinase (FAK), Akt (Ser473) and nuclear factor kappa B (NF-kB) p65. siRNA-mediated TNC knockdown ablated the migratory capacity of BT-474 NRP-1 cells and inactivated FAK/Akt473 signaling. NRP-1 overexpressing cells downregulated breast cancer resistance protein (BCRP/ABCG2). Consequently, sequential treatment with Adriamycin/Cyclophosphamide (AC) cytotoxic drugs to generate resistant cells indicated that BT-474 NRP-1 cells increased sensitivity to treatment by inactivating NRP-1/ITGB3/FAK/Akt/NF-kB p65 signaling compared to wild-type BT-474 resistant cells. We thus report a novel mechanism correlating high baseline NRP-1 with upregulated TNC/ITGB3 signaling, but decreased ABCG2 expression, which sensitizes BT-474 NRP-1 cells to Adriamycin/Cyclophosphamide. The study emphasizes on the targetability of the NRP-1/ITGB3 axis and its potential as a predictive biomarker for chemotherapy response.

The cancer testis antigen (CTA) lactate dehydrogenase C (LDHC) is a promising anticancer target with tumor‐specific expression and immunogenicity. Interrogation of breast cancer patient cohorts from The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) indicate that upregulation of LDHC expression correlates with unfavorable prognosis. Although the role of LDHC is well characterized in spermatocytes, its role in tumors remains largely unknown. We investigated whether LDHC is involved in regulating genomic stability and whether it could be targeted to affect tumor cellular fitness. Silencing LDHC in four breast cancer cell lines significantly increased the presence of giant cells, nuclear aberrations, DNA damage, and apoptosis. LDHC‐silenced cells demonstrated aberrant cell cycle progression with differential expression of cell cycle checkpoint and DNA damage response regulators. In addition, LDHC silencing‐induced microtubule destabilization, culminating in increased mitotic catastrophe and reduced long‐term survival. Notably, the clonogenicity of LDHC‐silenced cells was further reduced by treatment with the poly (ADP‐ribose) polymerase (PARP) inhibitor olaparib and with the DNA‐damaging drug cisplatin. This study supports the therapeutic potential of targeting LDHC to mitigate cancer cell survival and improve sensitivity to agents that cause DNA damage or inhibit its repair.