Metformin Inhibits The Progression Of Obesity-related Triple-negative Breast Cancer

Obesity and cancer are two common epidemics in this century.The rising prevalence of overweight and obesity worldwide has been substantial and widespread,and obesity has become a major global health challenge with more than 35%of the world's population having a body-mass index(BMI)of 25 kg/m~2 or greater.Several studies have reported an association of obesity with increased risk of recurrence and poorer overall and breast cancer-specific survival outcomes.The number of Chinese new breast cancer patients and the number of death reaches the world's 12.2%and 9.6%respectively every year,thus understanding which patients are at higher risk of relapse is of great importance.Obesity has been associated with increased risk and progression of a variety of cancer types including breast cancer,and about 20%of all deaths from cancer have been estimated to be attributable to excess weight in women above 50 years old in the US.Therefore,investigating the risk factor of breast cancer patients is particularly crucial for clinical treatment.Triple negative breast cancer(TNBC)is the most aggressive subtype with the worst prognosis and lack of targeted therapies hence new approaches for treating these patients are needed.Few studies have focused on the prognostic role of obesity in TNBC and the results vary considerably.Metformin is a drug commonly used for the treatment of type 2 diabetes.Epidemiologic,preclinical and ongoing clinical trials data point to an antitumor effect of metformin in breast cancer,with studies reporting higher pathologic complete response and better overall and cancer-specific survival time in breast cancer patients with diabetes taking metformin.The effect of metformin in TNBC is controversial,with some data reporting anti-cancer activity or tumor promoting effects in TNBC cells and clinical studies showing no effect in survival outcomes.Identifying which patients would benefit from metformin treatment is crucial to maximize its potential use in breast cancer.To further study the effect and machnism of obesity on triple negative breast cancer progression and the potencial posibility of metformin using in clinic for triple negative breast cancer,we combined patient derived xenograft(PDX)model and diet induced obesity(DIO)model to study the relationship among obesity,metformin and triple negative breast cancer.Our research demonstrated the results as below.1.We sucessfully established SCID beige-PDX2665 and C57BL/6-AT3 models and both of them are obese triple negative breast cancer mice model.The SCID beige-PDX2665 model illustrated whether diet or obesity has effect on tomor growth.2.Our result showed obesity can increase mice weight,body fat%,insulin level in serum,insulin resistant,the weight of gonadal white adipose tisse,the weight of interscapular brown adipose tissue,the weight of mammary gland as well we the weight of liver.We also found obesity can promote tumor progression and can whiten the adipose tissue.However,we didn't found difference of tumor proliferation by Ki67 and PHH3 staining and tumor necrosis.It has significant implication for the clinical TNBC treatment.3.We also used DIO model to study if metformin can alter triple negative breast cancer progression.The result showed in both HFD and CD groups metformin can decrease the mice weight and body fat%.Moreover,metformin can inhibit TNBC tumor growth which indicate metformin could be used as potencial drug for TNBC clincal trials.Here we used DIO mice model plus PDX mice model to create DIO-TNBC mice model which has not been done by others.In this in vivo experiment we found obesity can promote TNBC tumor growth.Metformin treatment reduced the tumor growth in the PDX model.This study revealed obesity has assciation with TNBC tumor growth and metformin has effect on TNBC tomor progression which is important as preclinical data.