Roles of proinflammatory chemokines linking obesity and breast cancer

 描述（由申请人提供）：肥胖在人群中迅速增加，是全球发病率和死亡率的主要可预防原因。肥胖会降低预期寿命，增加健康问题，包括心血管疾病、糖尿病和癌症。特别是，女性乳腺癌与肥胖密切相关。肥胖的人比瘦人更容易得癌症，癌症更严重，死于癌症的几率也更高。尽管肥胖和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，我们发现了一个促炎趋化因子与肥胖和乳腺癌有关。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加工来驱动炎症负荷。这最终是造成高死亡率的部分原因。该提案将定义肥胖促进的促炎趋化因子在乳腺癌进展中的作用。我们将使用CXCR 2基因敲除小鼠或肥胖小鼠，通过促炎趋化因子阐明肥胖引起的炎症负荷对乳腺癌进展的作用。由于与非TNBC细胞相比，三阴性乳腺癌（TNBC）细胞在响应炎症条件时产生增强水平的促炎趋化因子，我们将确定肥胖参与在TNBC细胞中产生这种更高促炎趋化因子负荷的分子机制。作为预防和治疗方法，我们将评价阿法替尼（抗表皮生长因子受体活化）和/或tempol（抗肥胖相关氧化应激）通过破坏肥胖促进的促炎趋化因子对乳腺癌进展的抗脂肪形成和抗肿瘤形成作用。这些发现将使我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生成和抗肿瘤生成作用的药物来改善女性癌症存活率的治疗策略，特别是对于肥胖癌症患者。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，并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.