Abstract
Clinically meaningful molecular subtypes for classification of breast cancers have been established, however, initiation and progression of these subtypes remain poorly understood. The recent development of desorption electrospray ionization-mass spectrometry imaging (DESI-MSI) facilitates the convergence of analytical chemistry and traditional pathology, allowing chemical profiling with minimal tissue pretreatment in frozen samples. Here, we characterized the chemical composition of molecular subtypes of breast cancer with DESI-MSI. Regions of interest were identified, including invasive breast cancer (IBC), ductal carcinoma in situ (DCIS), and adjacent benign tissue (ABT), and metabolomic profiles at 200 μm elaborated using Biomap software and the Lasso method. Top ions identified in IBC regions included polyunsaturated fatty acids, deprotonated glycerophospholipids, and sphingolipids. Highly saturated lipids, as well as antioxidant molecules [taurine (m/z 124.0068), uric acid (m/z 167.0210), ascorbic acid (m/z 175.0241), and glutathione (m/z 306.0765)], were able to distinguish IBC from ABT. Moreover, luminal B and triple-negative subtypes showed more complex lipid profiles compared with luminal A and HER2 subtypes. DCIS and IBC were distinguished on the basis of cell signaling and apoptosis-related ions [fatty acids (341.2100 and 382.3736 m/z) and glycerophospholipids (PE (P-16:0/22:6, m/z 746.5099, and PS (38:3), m/z 812.5440)]. In summary, DESI-MSI identified distinct lipid composition between DCIS and IBC and across molecular subtypes of breast cancer, with potential implications for breast cancer pathogenesis. SIGNIFICANCE: These findings present the first in situ metabolomic findings of the four molecular subtypes of breast cancer, DCIS, and normal tissue, and add to the understanding of their pathogenesis.
Highlights
Breast cancer is the most common cancer affecting women and represents a complex group of diseases that exhibit great variability at clinical presentation and biologic aggressiveness
Desorption electrospray ionization (DESI)-mass spectrometry imaging (MSI) has been able to distinguish benign from malignant metabolomic profiles [11] and was recently proven to be a reproducible technique for rapid breast cancer diagnosis [22]
We demonstrate the capacity of DESI-MSI to differentiate molecular subtypes of breast cancer, and to provide a better understanding of the metabolism inherent to particular regions of interest (ROI) in breast tissue
Summary
Breast cancer is the most common cancer affecting women and represents a complex group of diseases that exhibit great variability at clinical presentation and biologic aggressiveness. Numerous clinical studies of breast cancer coupled with advances in genomic profiling provided data that support the existence of clinically useful molecular subtypes [1]. Our understanding of initiation and progression of breast cancer remains incomplete. Cell processes driving invasiveness from ductal carcinoma in situ (DCIS) stage and differentiation into each molecular subtype of breast cancer are complex, and analyses beyond genomics are needed to better understand them. Metabolic reprogramming in cancer cells, referred to as the Warburg effect, was described nearly a century ago and the interest on this
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