Metabolomics of an endocrine-related breast cancer mouse model

ARAUJO, RITA; BISPO, DANIELA; LAMB, CAROLINE A.; FABRIS, VICTORIA; LANARI, CLAUDIA; HELGUERO, LUISA; GIL, ANA MARÍA

Taller; Oncometabolism: From Conceptual Knowledge to Clinical Applications; 2019

Breast cancer (BC) is the most common and deadliest type of cancer in women. In most cases, breast tumors are hormone-dependent (HD) and rely on steroid hormones (estrogen and progesterone) to activate intracellular receptors and stimulate tumor growth. However, with time almost half of breast cancer patients develop resistance to antagonist therapy. This process involves the progression of HD tumors to hormone-independent tumors (HI) and ultimately to tumor resistance to therapy (HIR). The full mechanism and pathways involved in this progression process remain unknown. Metabolic alterations are considered a hallmark of cancer progression and the altered metabolism in breast cancer has been intensively investigated by cancer metabolomics accentuating an emerging interest in understanding the interplay between tumor progression and aggressiveness and metabolic adaptations [1,2]In this work, we aimed to understand the metabolic interplay associated with the transition from HD to HI and HIR phenotypes and identify metabolic markers potentially useful to anticipate response to endocrine therapy. For this purpose, we applied an untargeted metabolomic strategy to characterize metabolic changes in the medroxyprogesterone acetate (MPA) mouse mammary carcinoma model, which has been refined to grow infiltrating mammary carcinomas that evolve through different stages of hormone dependence and therefore mimic human endocrine breast cancer progression (HD, HI and HIR) [3]. Polar metabolites were extracted from tumor tissue samples and analyzed by 1H-NMR (500 MHz) [4]. The principal component analysis (PCA) and partial least-squares discriminant analysis (PLS-DA) models derived from our data showed robust separations between HD, HI and HIR tumors and PLS-DA loading plots helped to identify lower levels of metabolites such as glutamic acid, glutamine, glycine, taurine, choline and glycerophosphocholine (among others) as specific for HI and HIR tumors, compared to HD. In addition, a set of metabolites was identified as apparently characteristics of resistance to therapy (high in HIR compared to HI), including a marked lactate increase. To assess the activity of MPA we also analyzed normal mammary tissue with and without the hormone. This analysis also helped understand if MPA influenced the differences found between HD and HI tumors.The observed distinguishing metabolic signatures of HD, HI and HIR tumors show that endocrine breast cancer exhibits distinct metabolomic patterns depending on the stage of aggressiveness and the altered metabolites found here may be the basis for the definition of biomarkers of endocrine-related breast tumors at different stages of progression and prognostic indicators of response to antagonist therapy.This study demonstrates the applicability of 1H-NMR metabolomics for understanding important metabolic alterations occurring during breast cancer progression and simultaneously determine direct effects of drug/tumor interactions.