HER2/neu and dietary fat: interactions in breast cancer

描述(申请人提供)：尽管在早期发现和治疗方面取得了重大进展，乳腺癌仍然是美国女性最常见的诊断癌症和第二大癌症死亡原因。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，针对特定肿瘤亚型开发创新的靶向治疗至关重要。HER-2/neu是一种受体酪氨酸激酶，它的过度表达定义了乳腺癌的一种分子亚型，与临床预后不良有关。我们在HER-2/neu转基因小鼠模型中的数据显示，与n-6多不饱和脂肪酸相比，饮食n-3多不饱和脂肪酸(PUFAs)显著抑制了乳腺肿瘤的发生，这表明HER-2/neu介导的致癌可能唯一容易受到饮食脂肪含量的影响。我们提出这个开发项目是为了研究饮食脂肪含量调节HER-2/neu阳性乳腺癌的机制。我们假设饮食中的n-3PUFAs通过破坏质膜上的关键相互作用来阻止HER-2/neu的激活和功能，从而抑制HER-2/neu诱导的乳腺癌的发生。为此，我们在体外和体内研究中制定了三个具体目标：1)确定n-3和n-6多不饱和脂肪酸在HER-2/neu诱导的乳腺癌发生过程中对HER-2/neu信号转导关键的蛋白-膜相互作用的影响；2)确定补充n-3和n-6 PUFA对乳腺癌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Fas和COX-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的基因-营养相互作用的更广泛的研究提供科学基础，识别HER-2/neu信号中易受n-3PUFA抑制的早期事件的生物标记物，可用于预防和治疗乳腺癌的饮食脂肪干预的临床试验。

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.