Author(s): Fonseca, Catarina Sofia Rodrigues dos Santos Granja da, 1979-
Date: 2015
Persistent ID: http://hdl.handle.net/10451/17946
Origin: Repositório da Universidade de Lisboa
Subject(s): Metabolismo; Neoplasias da mama; Progressão da doença; Colesterol; LDL-colesterol; Teses de doutoramento - 2015
Tese de doutoramento, Medicina (Cirurgia Geral), Universidade de Lisboa, Faculdade de Medicina, 2015
One in ten of all new cancers diagnosed worldwide, each year, is a breast cancer. Despite the more favorable survival of breast cancer patients in (high-incidence) developed regions due to screening, faster diagnosis and improved treatment, it remains the most frequent cause of cancer-related death in women. The research of the last decades focused primarily on tumor genomics considering the tumor as an entity independent of the organism. Although the personalized therapy has been the ultimate goal of this aproach, host characteristics were seldom valued. Our working hypothesis states that the tumor is a microsystem evolving within a host macrosystem and an- interdependence between them must exist. The concept of the influence of the macroenvironment in tumor development is consistent with the Darwinian theory of evolution that postulates selection as a fundamental property of biological systems. As environmental forces may explain breast cancer incidence patterns in the world population, host environmental factors may drive breast cancer phenotypes. Recent data indicate that some known risk factors for breast cancer are indeed systemic conditions such as obesity or diabetes. The epidemic prevalence of obesity and its associated comorbidities have been investigated as possible reasons for the increased incidence of cancer in Western societies. Although altered lipid profiles, including hypercholesterolemia, are extremely prevalent in these areas the role of systemic lipid metabolism in breast cancer is poorly understood. Lipids are fundamental to cells, where they act either as constituents of the cell or as cell signaling molecules. Cholesterol, in particular, is an essential component of cell membrane bilayer, where it concentrates on the so-called lipid rafts-membrane microdomains which are involved in cell polarity, migration, proliferation, survival and angiogenesis. Cholesterol is also an obligatory precursor of steroid hormones, such as estrogen and progesterone, being the vast majority of breast tumors hormone responsive. To date, most studies have seek to find a causal relation between cancer incidence and cholesterol plasma levels, however, fewer studies adressed a possible link in tumor aggressiveness or on its progression. Thus, for now, the importance of plasma cholesterol in breast cancer progression is largely unknown. This Thesis aimed to study the role of systemic cholesterol in breast cancer progression and the underlying molecular mechanisms. To do that, an observational prospective study was designed to follow a cohort of women with breast cancer (stages I-III), without previous treatment. Results show that plasma LDL-C at diagnosis positively correlates with tumor size and stage. At 2 years of follow up, higher levels of LDL-C were associated with reduced disease-free survival. These data indicate LDL-C as a biomarker of tumor aggressiveness (prognostic factor) and a possible therapeutic target (predictive factor). To demonstrate a causal implication of cholesterol-enriched environment in tumor progression, well established in vitro and in vivo models were used. Results revealed that LDL-C signaling induces a tumor phenotype, also observed in breast cancer patients characterized by increased cell proliferation and invasion. Cells exposed to higher LDL-C concentrations have distinct genetic expression, supporting an aggressive phenotype, as confirmed by gene expression analysis. It was also experimentally shown that tumor ABCA1 (main cellular membrane cholesterol exporter) expression in cholesterol-enriched environment is a marker of LDL-C induced phenotype. Together, the results of this thesis illustrate the influence of systemic metabolism in breast cancer progression and suggest that lipid profile must be assessed in all breast cancer patients. Being hypercholesterolemia so prevalent in Western societies with a global incidence pattern superimposing that of breast cancer, the modulation of cholesterol plasma levels are expected to have a major impact in (secondary) prevention. This seems particularly relevant for patients with hormone unresponsive tumors, for which no chemopreventive strategy exists.
Programa Gulbenkian de Formação Médica Avançada, Fundação Champalimaud
