Roles of proinflammatory chemokines linking obesity and breast cancer

 描述(申请人提供)：肥胖症在人口中迅速增加，是全球发病率和死亡率的主要可预防原因。肥胖降低了人们的预期寿命，增加了心血管疾病、糖尿病和癌症等健康问题。特别是，女性的乳腺癌与肥胖密切相关。肥胖的人比瘦的人得更多的癌症，更严重的癌症，死于癌症的几率更高。尽管肥胖与低癌症存活率之间存在流行病学联系，但人们对肥胖影响乳腺癌进展的分子机制知之甚少。最近，我们发现了一种促炎性趋化因子与肥胖和乳腺癌之间的联系。由于肥胖被认为是一种慢性炎症状态，脂肪细胞和乳腺癌细胞之间的串扰可以通过促进癌症进展的促炎趋化因子的阐述来驱动炎症负担。这最终在一定程度上导致了高死亡率。这项建议将确定肥胖促进的促炎趋化因子在乳腺癌进展中的作用。我们将通过使用CXCR2基因敲除或肥胖小鼠来阐明这种由肥胖衍生的炎症负担通过促炎趋化因子在乳腺癌进展中的作用。由于与非TNBC细胞相比，三阴性乳腺癌(TNBC)细胞在炎症条件下产生更高水平的促炎趋化因子，我们将确定肥胖参与在TNBC细胞中产生更高的促炎趋化因子负担的分子机制。作为一种预防和治疗方法，我们将通过破坏肥胖促进的促炎趋化因子来评估afatinib(抗表皮生长因子受体激活)和/或tempoll(抗肥胖相关氧化应激)在乳腺癌进展中的抗脂和抗肿瘤作用。这一发现将使人们更深入地了解促炎趋化因子在肥胖和乳腺癌进展中的作用。据设想，这些结果将建议通过具有抗脂肪和抗肿瘤作用的药物来提高女性癌症存活率的治疗策略，特别是对于肥胖的癌症患者。最后，预防和减少肥胖将为乳腺癌患者的长期生存提供坚实的基础，提高他们的生活质量。

 DESCRIPTION (provided by applicant): Obesity is increasing rapidly in the population and is a leading preventable cause of morbidity and mortality worldwide. Obesity reduces life expectancy and increases health problems including cardiovascular disease, diabetes and cancer. In particular, breast cancer in women is closely associated with obesity. Obese people get more cancer, worse cancer, and die more often from cancer than lean people. In spite of an epidemiological link between obesity and low cancer survival rates, little is known about the molecular mechanisms by which obesity affects the progression of breast cancer. Recently we identified a proinflammatory chemokine profile linking obesity and breast cancer. Because obesity is recognized as a chronic state of inflammation, crosstalk between adipocytes and breast cancer cells can drive the inflammatory burden via the elaboration of proinflammatory chemokines that promote cancer progression. This eventually is in part responsible for high mortality rates. This proposal will define the roles of obesity-promoted proinflammatory chemokines on the progression of breast cancer. We will clarify the role of this obesity-derived inflammatory burden via proinflammatory chemokines on the progression of breast cancer using CXCR2 knockout or obese mice. Because triple-negative breast cancer (TNBC) cells produce an enhanced level of proinflammatory chemokines in response to an inflammatory condition compared to non-TNBC cells, we will determine the molecular mechanisms by which obesity is involved in producing this higher proinflammatory chemokine burden in TNBC cells. As a preventive and therapeutic approach, we will evaluate the anti- adipogenic and anti-tumorigenic effects of afatinib (against epidermal growth factor receptor activation) and/or tempol (against obesity-related oxidative stress) on the progression of breast cancer via disruption of obesity- promoted proinflammatory chemokines. The findings will provide a deeper understanding of the role of proinflammatory chemokines that link obesity and the progression of breast cancer. It is envisaged that the results will suggest therapeutic strategies to improve women cancer survival, particularly for obese cancer patients, through drugs with anti-adipogenic and anti-tumorigenic effects. Finally, preventing and reducing obesity will provide a firm foundation for long-term survival of breast cancer patients and improve their quality of life.