Proteomics of Genetically Engineered Mouse Mammary Tumors Identifies Fatty Acid Metabolism Members as Potential Predictive Markers for Cisplatin Resistance

Abstract

In contrast to various signatures that predict the prognosis of breast cancer patients, markers that predict chemotherapy response are still elusive. To detect such predictive biomarkers, we investigated early changes in protein expression using two mouse models for distinct breast cancer subtypes who have a differential knock-out status for the breast cancer 1, early onset ( Breast cancer is a heterogeneous disease consisting of a variety of subtypes that need different treatment strategies. In contrast to several prognostic signatures for clinical outcome, markers that predict treatment efficacy have been difficult to define. Reasons to explain this failure have been discussed elsewhere (1). A shortcoming of previous attempts to identify such markers may be that tumors were usually not challenged by drugs when sampled for analysis, or treatment was given a few weeks before sampling (neoadjuvant trials). Moreover, most previous studies focused on the analysis of gene expression to identify useful markers. However, differential expression of relevant factors, such as those involved in the DNA damage response, may be easier to detect shortly after chemotherapy-induced stress, and protein level readouts may provide a more direct way of assessing drug response.In this study, we aimed at detecting predictive biomarkers at the protein level by comparing the short term treatment response of platinum-sensitive versus platinum-resistant mouse mammary tumors that represent different breast cancer subtypes. As a sensitive model, we used the K14cre; Brca1 F/F ;p53 F/F mouse model (2) for BRCA1 1 -deficient breast cancer. The Brca1 Ϫ/Ϫ ;p53 Ϫ/Ϫ tumors that arise in this model include a large intragenic deletion of Brca1, and we have previously shown that these tumors are highly sensitive to cisplatin treatment (3). The response that we observed in this mouse model is consistent with the sensitivity of BRCA1-like breast cancer to intensive platinum-based chemotherapy in the clinic (4). Moreover, it was recently shown that triplenegative breast cancer patients frequently respond to cisplatin treatment, especially in patients with lower BRCA1 expression (5).As resistant model, we chose WAPcre;Cdh1 F/F ;p53

Fatty Acids and Breast Cancer: Make Them on Site or Have Them Delivered

“…Moreover, the fluidity of saturated membranes was affected in a manner that caused reduced uptake of the cytotoxic chemotherapeutic agent doxorubicin. In line with this observation, a lipogenic proteomics signature was associated with cisplatin resistance in a mouse BC model (Warmoes et al, ). Sounni et al () noted that enhanced glycolysis and lipogenesis occurred in resurgent tumors following the withdrawal of anti‐angiogenic therapy in mouse cancer models, including BC.…”

The effect of FASN inhibition on the growth and metabolism of a cisplatin‐resistant ovarian carcinoma model

“…A combination of cerulenin and 5‐fluorouracil displayed a schedule‐dependent synergistic effect in breast carcinoma cells with maximum efficacy when cells were exposed to 5‐fluorouracil prior to cerulenin . A proteomic analysis of cisplatin‐resistant mouse mammary tumours identified FASN as a predictive marker for cisplatin resistance; inhibition of FASN sensitised resistant cells to cisplatin . Inhibiting key metabolic enzymes in the fatty acid synthesis pathway led to significant cell death in cisplatin‐resistant lung cancer cells .…”

“…43 A proteomic analysis of cisplatin-resistant mouse mammary tumours identified FASN as a predictive marker for cisplatin resistance; inhibition of FASN sensitised resistant cells to cisplatin. 44 Inhibiting key metabolic enzymes in the fatty acid synthesis pathway led to significant cell death in cisplatinresistant lung cancer cells. 45 In addition, combination treatment of C75 and cisplatin resulted in growth inhibition of epithelial ovarian carcinoma xenografts in nude mice.…”

The Metabolic Alterations of Cancer Cells

“…However, SCD is an oxygen-dependent enzyme; therefore, under hypoxic conditions, its enzymatic activity could be greatly reduced. Furthermore, high degree of lipid saturation correlates with increased vertical and horizontal movement of lipids in the membrane, leading to reduced uptake of chemotherapeutic agents into cells (Warmoes et al, 2013). Importantly, hypoxic cells become dependent on extracellular unsaturated lysophospholipids to overcome SCD deregulation .…”