Abstract
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.
Highlights
Breast cancer (BC) accounts for nearly 25% of diagnosed cancer cases in women worldwide, causing the highest number of deaths by cancer in this population
Compared to previous nuclear magnetic resonance (NMR) reports of aqueous extracts from mouse and rat mammary tumors [20, 24, 27] and high-resolution magic angle spinning (HRMAS) NMR of human breast tumor tissue [28–30], all metabolites hereby identified in the medroxyprogesterone acetate (MPA)-induced tumors have been observed previously in different types of BC tissue, with the exception of adipate, ascorbate and hypoxanthine, which could not be detected here
Understanding the metabolite changes during cancer progression is relevant for diagnosis, follow-up and treatment, this study addresses three mammary invasive ductal adenocarcinoma tumour lines that express similar levels of ER and progesterone receptor (PR) but respond differently to Endocrine therapy (ET) [21], with the aim of characterising the metabolic profiles of neoplastic tissue compared to normal tissue (MG), and disclosing metabolic signatures discriminative of HD, HI and HIR tumors
Summary
Breast cancer (BC) accounts for nearly 25% of diagnosed cancer cases in women worldwide, causing the highest number of deaths by cancer in this population. Since HRpositive breast tumors depend on activation of ERa to sustain growth, most endocrine therapies target the ER signalling pathway [2]. Current therapeutic strategies include blocking ERa transcriptional activity with tamoxifen or fulvestrant, and blocking estrogen conversion in peripheral tissues with aromatase inhibitors [3]. PR can sustain tumor growth and, endocrine therapies targeting PR are beginning to be used in selected cases [4–6]. The vast majority of BC patients initially respond to endocrine therapy (ET), about 30-50% eventually relapse (acquired resistance), while ca. There is an interest in characterizing metabolic changes associated with endocrine resistance, which may be developed into predictive markers to assist the patient at diagnosis and help the implementation of personalized follow-up schemes
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