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

ARAÚJO, RITA; FABRIS, VICTORIA; LAMB, CAROLINE A.; LANARI, CLAUDIA; HELGUERO, LUISA A.; GIL, ANA M.

Frontiers in Oncology

Frontiers

Año: 2022 vol. 12

Breast cancer (BC) is the most common type of cancer in women and, in most cases, it ishormone-dependent (HD), thus relying on ovarian hormone activation of intracellularreceptors to stimulate tumor growth. Endocrine therapy (ET) aimed at preventing hormonereceptor activation is the primary treatment strategy, however, about half of the patients,develop resistance in time. This involves the development of hormone independenttumors 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 andnot completely understood. The aim of this work was to characterize the metabolicadaptations accompanying this conversion through the analysis of the polar metabolomesof tumor tissue and non-compromised mammary gland from mice implantedsubcutaneously 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 andunivariate statistical analysis. Initial results unveiled marked changes between global tumorprofiles and non-compromised mammary gland tissues, as expected. More importantly,specific metabolic signatures were found to accompany progression from HD, through HIand to HIR tumors, impacting on amino acids, nucleotides, membrane percursors andmetabolites related to oxidative stress protection mechanisms. For each transition, sets ofpolar metabolites are advanced as potential markers of progression, including acquisitionof resistance to ET. Putative biochemical interpretation of such signatures are proposedand discussed.