HER2/neu and dietary fat: interactions in breast cancer

描述（由申请人提供）：乳腺癌仍然是最常见的诊断癌症和美国妇女癌症死亡的第二大原因，尽管在早期检测和治疗方面取得了重大进展。乳腺癌的遗传和分子异质性对治疗和预防策略提出了挑战，针对特定肿瘤亚型的创新靶向治疗的开发至关重要。HER-2/neu（一种受体酪氨酸激酶）的过表达定义了与不良临床结局相关的乳腺癌分子亚型。我们在HER-2/neu转基因小鼠模型中的数据显示，与n-6多不饱和脂肪酸（PUFA）相比，饮食n-3多不饱和脂肪酸（PUFA）对乳腺肿瘤发生有明显的抑制作用，这表明HER-2/neu介导的致癌作用可能对饮食脂肪含量特别敏感。我们正在提出这个发展项目，以调查膳食脂肪含量调节HER-2/neu阳性乳腺癌的机制。我们假设，饮食n-3 PUFA抑制HER-2/neu诱导的乳腺癌的发生，通过阻止HER-2/neu激活和功能，通过破坏质膜上的关键相互作用。为此，我们开发了体外和体内研究的三个具体目标：1）确定在HER-2/neu诱导的乳腺癌发生过程中，n-3和n-6 PUFA对HER-2/neu信号传导关键的蛋白-膜相互作用的影响; 2）鉴定n-3和n-6 PUFA补充对乳腺癌中HER-2/neu介导的信号转导的影响;以及3）确定膳食脂肪含量对乳腺癌中FAS和考克斯-2表达的影响，作为HER-2/neu活性的潜在替代生物标志物。这一建议将为乳腺癌中这种新型基因-营养相互作用的更广泛研究提供科学依据，并确定对n-3 PUFA抑制敏感的HER- 2/neu信号传导早期事件的生物标志物，可用于乳腺癌预防和治疗的膳食脂肪干预临床试验。

DESCRIPTION (provided by applicant): Breast cancer remains the most commonly diagnosed cancer and second leading cause of cancer deaths in American women, despite significant advances in early detection and treatment. The genetic and molecular heterogeneity of breast cancer represents a challenge for treatment and prevention strategies, and the development of innovative targeted therapies for specific tumor subtypes is essential. Overexpression of HER-2/neu, a receptor tyrosine kinase, defines a molecular subtype of breast cancer associated with poor clinical outcome. Our data in the HER-2/neu transgenic mouse model show marked suppression of mammary tumorigenesis by dietary n-3 polyunsaturated fatty acids (PUFAs) compared to n-6 PUFAs, suggesting that HER-2/neu-mediated carcinogenesis might be uniquely susceptible to dietary fat content. We are proposing this developmental project to investigate the mechanisms by which dietary fat content modulates HER-2/neu-positive breast cancer. We hypothesize that dietary n-3 PUFAs inhibit HER-2/neuinduced mammary carcinogenesis by preventing HER-2/neu activation and function through disruption of critical interactions at the plasma membrane. To this end, we developed three specific aims for in vitro and in vivo studies to: 1) determine the effects of n-3 and n-6 PUFAs on protein-membrane interactions critical to HER-2/neu signaling during HER-2/neu-induced mammary carcinogenesis; 2) identify the effects of n-3 and n-6 PUFA supplementation on HER-2/neu-mediated signal transduction in breast cancer; and 3) define the effects of dietary fat content on the expression of FAS and COX-2 in breast cancer, as potential surrogate biomarkers of HER-2/neu activity. This proposal will provide the scientific basis for more extended studies of this novel gene-nutrient interaction in breast cancer, with identification of biomarkers of early events in HER- 2/neu signaling susceptible to n-3 PUFA suppression that can be used in clinical trials of dietary fat nterventions for breast cancer prevention and treatment.