Role of leptin in the pathogenesis of breast cancer / Papel da leptina na patogênese do câncer de mama

A leptina é um pequeno polipeptídeo codificado pelo gene OB, profundamente relacionado com a massa de gordura corporal e o balanço energético. Devido aos seus diversos efeitos biológicos e transdutores de sinal regulados, múltiplas classificações biológicas tem sido atribuídas à leptina, incluindo hormônio,citocina, adipocina, fator de crescimento, e fator de desenvolvimento, dentre outros. Este cenário nos dá uma idéia do tamanho do potencial de efeitos biológicos gerados por esta molécula. A concentração de leptina no corpo é determinada pela quantidade de tecido adiposo; portanto, hiperleptinemia é um achado comum em indivíduos obesos. Além disso, níveis elevados de leptina circulante pode conferirum pior prognóstico para qualquer condição patológica. Apesar da história da leptina ter sido reportada por mais de 20 anos, sua relação com o câncer ganhou notoriedade nos últimos 10 anos, quando estudos focaram e discutiram o papel da obesidade com um forte fator de risco para o desenvolvimento de câncer.Adicionalmente, evidências crescentes apontam a leptina como mediador primordial da resposta imune, oque agrava o cenário da ocorrência de câncer na presença de obesidade. Assim, a leptina pode apresentar pelo menos duas faces na patogênese do câncer, agindo através de mecanismos imunológicos e não imunológicos.Neste trabalho, revisamos a dinâmica do eixo leptina no câncer de mama e discutimos seu papel na doença, imunopatogênese e prognóstico.

Leptin is a small polypeptide codified by the Obese Gene (OB), deeply related with the body fat massand energetic balance. Due to its diverse biological effects and downstream signal transducers, multipleclassifications have been attributed to leptin, as hormone, cytokine, adypokine, growth factor, anddevelopmental factor, among others. This scenario gives us an idea of the size of the potential biological effects generated by this molecule. The concentration of leptin in the body is determined by the amountof adipose tissue; the refore, hyperleptinemia is a common finding in obese individuals. In addition, highlevels of circulating leptin may confer a poor prognosis for any pathological condition. Although leptin history has been reported for more than 20 years, its relationship with cancer has gained notoriety in the past ten years, where studies focused on discussing the issue of obesity as a strong risk factor for cancer developing. Further, growing evidences have pointed leptin as a pivotal mediator of immune response, which aggravates the scenario of cancer occurrence in the presence of obesity. Therefore, leptin can present at least two faces in the pathogenesis of breast cancer, acting by immune and non-immune mechanisms. In this paper we review the dynamic of the leptin axis in breast cancer and further discussits role in disease, immunopathogenesis and prognosis.

Mecanismos de proliferação celular dependentes da atividade do coativador - 1 de receptor ativado por proliferadores de peroxissoma gama (PGC-1) / Mechanisms of cellular proliferation dependent on peroxisome proliferator-activated receptor-gamma coactivator 1 (PGC-1)

Apesar dos avanços no tratamento dos diferentes subtipos moleculares do câncer de mama, diversos efeitos colaterais e resistência ao tratamento são observados. Nesse contexto, a busca por novos marcadores moleculares ainda é necessária. A família do coativador - 1 do receptor ativado por proliferadores de peroxissoma gama-1 (PGC-1) exerce funções cruciais no metabolismo energético celular e alguns trabalhos na literatura mostram alterações de PGC-1 no desenvolvimento do câncer. Contudo, mecanismos envolvidos na proliferação celular do carcinoma de mama permanecem desconhecidos. O objetivo geral foi determinar os mecanismos pelos quais PGC-1 controla a proliferação de células tumorais de mama, com foco em vias metabólicas e de sinalização redox. Para alcançar os objetivos, foi determinada a expressão de PGC-1alfa e beta em células tumorais de mama dos subtipos moleculares luminal (MCF-7), HER2- superexpresso (SKBR3) e triplo negativo (MDAMB231) em relação a uma linhagem de mama não tumoral (MCF-10A). Foi encontrada maior expressão gênica e proteica de PGC-1beta na superexpressão de HER2, e maior taxa de crescimento para essa linhagem. Para investigar se PGC-1beta pode estar envolvido na proliferação dessas células, utilizamos sequências específicas de RNA de interferência para o knockdown de PGC-1beta nas células SKBR3. Após o tratamento houve diminuição de proliferação celular. Assim, investigamos os prováveis mecanismos pelos quais PGC-1beta diminui a proliferação celular. Nossos resultados mostram que o knockdown de PGC-1beta não influenciou a expressão de ciclinas (B, C, D e E) e não houve diferença na quantidade de DNA mitocondrial, fator de transcrição mitocondrial A (TFAM), fator de respiração nuclear (NRF) 1 e 2. Em seguida, mostramos que o knockdown de PGC-1beta diminuiu a produção de lactato intracelular e aumentou a atividade da enzima citrato sintase, e houve tendência a maior taxa de respiração celular. Detectamos maiores...

Despite a marked improvement in treatments for all breast cancer subtypes, several side-effects and resistance to therapy are noticed. In this context, the searching for new molecular targets for breast cancer treatment is still a challenge. Peroxisome proliferator-activated receptor- gamma coactivator 1 (PGC-1) is the main regulator of cell energy homeostasis and studies in the literature show alterations regarding PGC-1 in cancer development. However, mechanisms involved in cellular proliferation of breast cancer remain unknown. We aimed to determine the mechanisms by which PGC-1beta controls breast cancer cell proliferation, focusing on metabolic and redox signaling. To reach this goal, we determined PGC-1alfa and beta expression in breast cancer cell lines as luminal (MCF-7), HER2-overexpressed (SKBR3) and triple- negative (MDAMB231) as compared to a non-tumoral breast cell line (MCF-10A). We found increased gene and protein expression of PGC-1beta in HER2- overexpressed cells and increased cellular proliferation. To investigate whether PGC-1beta could be involved in the proliferation of those cells, we used specific sequences of silencing interfering RNA for knockdown of PGC-1beta in SKBR3 cells. After treatment we observed a decrease in cellular proliferation. Thus, we next investigated the probable mechanisms by which PGC-1beta could decrease cellular proliferation. Our results showed that knockdown of PGC-1beta did not influence on cyclin expression (B, C, D and E), mitochondrial DNA number, mitochondrial transcription factor - A (TFAM), nuclear receptor factor (NRF) 1 and 2 expression. We showed that knockdown of PGC-1beta induced a decrease intracellular lactate production, increase in citrate synthase activity and a trend to increase cellular respiration rate. Thereby, we detected greater amounts of reactive oxygen species (ROS) after knockdown of PGC-1beta, and no alterations was found for nitrite and nitrate levels. No alterations regarding...

Smoking as a risk factor for the development of breast cancer

INTRODUCTION: Smoking is considered a public health problem and in many cases is responsible for the development of lung diseases and cancer. One of the mechanisms by which tobacco can induce cancer is through the generation of free radicals, establishing an oxidative stress status in smokers. With increasing smoking among women, much evidence in the literature has shown a relation between smoking and breast cancer development. OBJECTIVE: The aim of this review was to analyze the available studies in literature that demonstrate the association between smoking and the risk of breast cancer development. METHODS: We performed a review from the literature based on the search results in PubMed and Scielo. The selected works were composed by current articles according to their relevance and human application. RESULTS: The literature revealed several published studies linking smoking to oxidative stress through the action of free radicals that are generated by toxic compounds found in cigarettes. There are few studies relating smoking with breast cancer, which is a relatively more recent research line, where the vast majority of works includes epidemiological and controversial studies. CONCLUSIONS: The selected works show that, although controversial, smoking is considered a risk factor for developing breast cancer.

Aspects related to oxidative stress-mediated toxicity of doxorubicin during chemotherapy treatment

OBJECTIVE: This study aimed to describe the main toxic effects mediated by oxidative stress associated with treatment with doxorubicin in scientific research articles available in the literature. MATERIAL AND METHODS: This study employed a descriptive review methodology applied to the literature. For the theoretical scientific background, we used the electronic PubMed search engines. CONCLUSION: The toxicity of chemotherapy treatment with doxorubicin causes damage in various organs of patients who are in uninterrupted treatment with this antineoplastic agent. Anthracycline-induced cardiotoxicity has been investigated to a great degree and is especially indicated as the principal side effect. Therefore, care needs to be given to other damage caused by this medication as important as myocardial toxicity, such as renal, pulmonary and liver toxicity, among others. There is a need for further studies to prevent or even encounter a way to control the damage caused by these toxicities in various tissues.

Breast cancer and oxidative stress in chemotherapy

Objective: This revision characterizes the biomarkers used for analysis of the development of oxidative stress produced during breast cancer chemotherapy. Materials and methods: A search of articles indexed in digital databases (Lilacs, Bireme, PubMed, Scielo and digital libraries), along with publications printed as books, periodicals and articles not available online, in the period from 1979 to 2009. Conclusion: Reactive oxygen and nitrogen species are produced, principally, during aerobic metabolism; however, its synthesis can be exacerbated or antioxidant defense reduced or more usually, both conditions can occurr in many pathophysiologic situations, leading to a net reactive species yelded. This unbalance is defined as oxidative stress. Stress biomarkers can be defined as predictive indicators able to detect in vivo oxidative damage and can be subdivided into antioxidant and pro-oxidants. To verify the antioxidant system, it is possible to analyze the superoxide dismutase enzymes, catalase and glutathione, along with vitamins A, E, C and glutathione among others. The analysis of pro-oxidants can be made through the verification of protein nitration and oxidation, heat shock proteins, lipoperoxidation, formation of aldehydes for malondialdehyde tests, 4-hydroxynonenal, oxidized LDL and isoprostanes or for chemiluminescent techniques. Advances in cancer detection through the identification of potential biomarkers consist of a promising strategy for the prevention and early identification of this pathology.