FATTY ACIDS AND HUMAN BREAST CANCER GROWTH

描述：该项目的长期目标是确定如何 饮食中的脂肪酸影响乳腺癌的进展。次要的 目标是开发饮食干预和 以适当的方式抑制这一进展的药理药物 动物模型。短期目标是：第一，进一步探索 膳食脂肪酸、脂氧合酶产物和 蛋白水解酶在侵袭过程中的表达；第二，延伸 这些研究包括脂氧合酶产物介导的蛋白质激活 蛋白激酶C(PKC)；第三，确定不良侵袭性和转移性 雌激素受体阳性乳腺癌细胞株的能力相关 到低水平的12-脂氧合酶(12-LOH)活性和受损 12-羟基-四烯酸(12-HETE)的合成。第一个具体 目的确定n-6和n-3脂肪酸在肿瘤转移中的作用。 人乳腺MDA-MB-231和MDA-MB-435雌激素非依赖性的潜能 裸鼠体内的癌细胞。第二个具体目标是测试 雌激素非依赖性乳腺癌细胞进展为更多 高转移性表型与表达增强相关 12-LOX诱导的波形蛋白和蛋白水解酶活性 通过12-HETE介导的PKC激活而激活。申请人建议： 在体外和体内对这一假设进行评估。在建议的 体外研究，不同程度雌激素作用的乳腺癌细胞株 依赖性和独立性将被检查和比较是否具有侵入性 活性、波形蛋白和蛋白水解酶的表达以及PKC的活性 在n-6个氨基酸(LA和AA)中，12-HETE也将在 转移表型的这些化合物的表达。此外， 同样的细胞系将在裸鼠的乳房脂肪垫中生长， 体内自发性转移能力的比较。

DESCRIPTION: The long term objective of this project is to determine how dietary fatty acids influence the progression of breast cancer. A secondary objective is to develop combinations of dietary interventions and pharmacological agents which suppress this progression in an appropriate animal model. The short term goals are: first, to explore further interrelations between dietary fatty acids, lipoxygenase products, and proteolytic enzyme expression in the invasive process; second, to extend these studies to include lipoxygenase product-mediated activation of protein kinase (PKC); third, to determine whether the poor invasive and metastatic capability of estrogen receptor positive breast cancer cell lines is related to a low level of 12-lipoxygenase (12-LOH) activity and impaired 12-hydroxyeicosa-tetraenoic acid (12-HETE) synthesis. The first specific aim will determine the effects of n-6 and n-3 fatty acids on the metastatic potential of MDA-MB-231 and MDA-MB-435 estrogen-independent human breast cancer cells in nude mice. The second specific aim is to test the hypothesis that estrogen independent breast cancer cells progress to a more highly metastatic phenotype that is associated with enhanced expression of vimentin and proteolytic activity as a consequence of an induction of 12-LOX activity through 12-HETE-mediated PKC activation. The applicant proposes to evaluate this hypothesis both in vitro and in vivo. In the proposed in vitro studies, breast cancer cell lines with different degrees of estrogen dependence and independence will be examined and compared for invasive activity, vimentin and protease expression, and PKC activity for the effects of the n-6 amino acids (LA and AA), also, 12-HETE will be assessed on the expression of these compounds of the metastatic phenotype. In addition, the same cell lines will be grown in the mammary fatpad of nude mice and the capacity for spontaneous metastases compared in vivo.