Metabolic Adaptations in an Endocrine-Related Breast Cancer Mouse Model Unveil Potential Markers of Tumor Response to Hormonal Therapy


Breast cancer (BC) is the most common type of cancer in women and, in most cases, it is hormone-dependent (HD), thus relying on ovarian hormone activation of intracellular receptors to stimulate tumor growth. Endocrine therapy (ET) aimed at preventing hormone receptor activation is the primary treatment strategy, however, about half of the patients, develop resistance in time. This involves the development of hormone independent tumors that initially are ET-responsive (HI), which may subsequently become resistant (HIR). The mechanisms that promote the conversion of HI to HIR tumors are varied and not completely understood. The aim of this work was to characterize the metabolic adaptations accompanying this conversion through the analysis of the polar metabolomes of tumor tissue and non-compromised mammary gland from mice implanted subcutaneously with HD, HI and HIR tumors from a medroxyprogesterone acetate (MPA)-induced BC mouse model. This was carried out by nuclear magnetic resonance (NMR) spectroscopy of tissue polar extracts and data mining through multivariate and univariate statistical analysis. Initial results unveiled marked changes between global tumor profiles and non-compromised mammary gland tissues, as expected. More importantly, specific metabolic signatures were found to accompany progression from HD, through HI and to HIR tumors, impacting on amino acids, nucleotides, membrane percursors and metabolites related to oxidative stress protection mechanisms. For each transition, sets of polar metabolites are advanced as potential markers of progression, including acquisition of resistance to ET. Putative biochemical interpretation of such signatures are proposed and discussed.



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Araujo, R; Fabris, V; Lamb, CA; Lanari, C; Helguero, LA; Gil, AM

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This work was developed within the scope of the project CICECO-Aveiro Institute of Materials, UIDB/50011/2020, UIDP/50011/2020 & LA/P/0006/2020, financed by national funds through the FCT/MEC (PIDDAC). AG acknowledges the Portuguese National NMR Network (RNRMN), supported by FCT funds, and RA thanks RNRMN for her grant through the Doctoral Program in NMR applied to Chemistry, Materials and Biosciences -PTNMRPhD (PD/00065/2013). The authors also acknowledge financial support from the Portuguese Foundation for Science and Technology through projects UIDB/04501/2020, UIDP/04501/2020, MEDISIS (CENTRO-01-0246-FEDER000018) and pAGE (CENTRO-01-0145-FEDER-000003) project cofounded through the Comissao de Coordenacao e Desenvolvimento Regional do Centro and COMPETE 2020 program and European Union fund FEDER (LH). The authors also acknowledge the Agencia Nacional de Promocion Cientifica y Tecnologica, Argentina (ANPCYT); grant PICT 20172073 (CL).

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