Publicação
Metabolomics of an endocrine-related breast cancer mouse model to study cancer progression and therapy resistance
| Resumo: | Breast cancer (BC) remains one of the most prevalent cancers, with the hormone receptor-positive (HR+) subtype constituting about 70% of cases. In most instances, these tumors are hormone-dependent (HD). Despite advances in endocrine therapies (ET), resistance to these treatments poses a critical challenge. ET resistance involves the development of hormone-independent tumors that are initially responsive to ET (HI) but may subsequently become resistant (HIR). The mechanisms driving the conversion of HI to HIR tumors are diverse and not fully understood. The aim of this thesis included: i) investigating tissue stability at room temperature (RT), focusing on HI mammary tumor and tissues from various organs to obtain recommendations for standard operating procedures for handling tissues at RT; ii) characterizing metabolic differences in the endo and exometabolome of HR+ BC cell lines (MCF-7 cell line and its tamoxifen (Tam)-resistant derivative, MCF-7R) and their response to the first-line ET, Tam; iii) characterizing metabolic adaptations accompanying the progression from HD to HI and subsequently to HIR tumors; and finally iv) characterizing the metabolic adaptations of HI and HIR tumors treated with an antiprogestin, mifepristone (MF); using NMR metabolomics of mammary tumors from a medroxyprogesterone acetate (MPA)-induced BC mouse model. Chapter I of this thesis provides a framework for the work, beginning with BC classification and therapy options, as well as addressing BC therapy resistance. It also includes a description of NMR metabolomics principles and a review of BC metabolomics studies in murine models. Chapter III explores the stability of HI mammary tumor, liver, lung, spleen, and uterus and ovaries system tissues at RT, demonstrating that different tissues exhibit different susceptibilities to thawing. Chapter IV investigates the effects of Tam treatment on MCF-7 and MCF-7R cell lines, addressing changes in both the endometabolome and exometabolome, and providing a comprehensive view of therapy response and resistance. Our results reveal altered pathways in MCF-7R cells as potential therapeutic targets to enhance ET efficacy. Chapter V explores the metabolic changes associated with the progression from HD to HI and HIR tumors. Our results identified characteristic metabolic signatures for HD, HI, and HIR tumors, providing important insights into metabolic adaptations occurring during resistance. Chapter VI focuses on the metabolic adaptations of HI and HIR tumors when treated with MFP. Our results indicate that MFP had a less pronounced impact on the polar metabolome of HIR tumors, while, in contrast, the lipid metabolome of HIR tumors exhibited greater changes in response to MFP compared to HI tumors. This chapter highlights the potential of MFP in altering metabolic pathways associated with therapeutic resistance. Finally, Chapter VII summarizes the conclusions of this work and outlines perspectives for future research. |
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| Autores principais: | Silva, Ana Rita Araújo |
| Assunto: | Breast cancer Hormone receptors Progesterone receptor (PR) Therapy Resistance Metabolomics Nuclear magnetic resonance (NMR) spectroscopy |
| Ano: | 2024 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso embargado |
| Instituição associada: | Universidade de Aveiro |
| Idioma: | inglês |
| Origem: | RIA - Repositório Institucional da Universidade de Aveiro |
| Resumo: | Breast cancer (BC) remains one of the most prevalent cancers, with the hormone receptor-positive (HR+) subtype constituting about 70% of cases. In most instances, these tumors are hormone-dependent (HD). Despite advances in endocrine therapies (ET), resistance to these treatments poses a critical challenge. ET resistance involves the development of hormone-independent tumors that are initially responsive to ET (HI) but may subsequently become resistant (HIR). The mechanisms driving the conversion of HI to HIR tumors are diverse and not fully understood. The aim of this thesis included: i) investigating tissue stability at room temperature (RT), focusing on HI mammary tumor and tissues from various organs to obtain recommendations for standard operating procedures for handling tissues at RT; ii) characterizing metabolic differences in the endo and exometabolome of HR+ BC cell lines (MCF-7 cell line and its tamoxifen (Tam)-resistant derivative, MCF-7R) and their response to the first-line ET, Tam; iii) characterizing metabolic adaptations accompanying the progression from HD to HI and subsequently to HIR tumors; and finally iv) characterizing the metabolic adaptations of HI and HIR tumors treated with an antiprogestin, mifepristone (MF); using NMR metabolomics of mammary tumors from a medroxyprogesterone acetate (MPA)-induced BC mouse model. Chapter I of this thesis provides a framework for the work, beginning with BC classification and therapy options, as well as addressing BC therapy resistance. It also includes a description of NMR metabolomics principles and a review of BC metabolomics studies in murine models. Chapter III explores the stability of HI mammary tumor, liver, lung, spleen, and uterus and ovaries system tissues at RT, demonstrating that different tissues exhibit different susceptibilities to thawing. Chapter IV investigates the effects of Tam treatment on MCF-7 and MCF-7R cell lines, addressing changes in both the endometabolome and exometabolome, and providing a comprehensive view of therapy response and resistance. Our results reveal altered pathways in MCF-7R cells as potential therapeutic targets to enhance ET efficacy. Chapter V explores the metabolic changes associated with the progression from HD to HI and HIR tumors. Our results identified characteristic metabolic signatures for HD, HI, and HIR tumors, providing important insights into metabolic adaptations occurring during resistance. Chapter VI focuses on the metabolic adaptations of HI and HIR tumors when treated with MFP. Our results indicate that MFP had a less pronounced impact on the polar metabolome of HIR tumors, while, in contrast, the lipid metabolome of HIR tumors exhibited greater changes in response to MFP compared to HI tumors. This chapter highlights the potential of MFP in altering metabolic pathways associated with therapeutic resistance. Finally, Chapter VII summarizes the conclusions of this work and outlines perspectives for future research. |
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