FATTY ACIDS AND HUMAN BREAST CANCER GROWTH

描述：本项目的长期目标是确定如何 膳食脂肪酸影响乳腺癌的进展。 次级 目标是制定饮食干预措施的组合， 以适当的方式抑制这种进展的药物 动物模型 近期目标是：一是进一步探索 膳食脂肪酸、脂氧合酶产物和 蛋白水解酶在侵入过程中的表达;第二， 这些研究包括脂氧合酶产物介导的蛋白质活化 激酶（PKC）;第三，判断是否有不良的侵袭和转移 雌激素受体阳性乳腺癌细胞系的能力相关 低水平的12-脂氧合酶（12-洛）活性， 12-羟基二十碳四烯酸（12-HETE）合成。 第一特定 目的是确定n-6和n-3脂肪酸对转移性肿瘤的影响。 MDA-MB-231和MDA-MB-435非雌激素依赖性人乳腺癌的潜力 裸鼠体内的癌细胞。 第二个具体目标是测试 假设雌激素非依赖性乳腺癌细胞进展到一个更高的水平， 高转移性表型，其与增强的 波形蛋白和蛋白水解活性作为12-LOX诱导的结果 通过12-HETE介导的PKC激活的活性。 申请人建议 在体外和体内评估这一假设。 在建议中， 体外研究表明，乳腺癌细胞系中含有不同程度的雌激素 独立性和依赖性将被检查和比较， 活性、波形蛋白和蛋白酶表达以及PKC活性的影响 在n-6氨基酸（LA和AA）中，也将在 转移表型的这些化合物的表达。 此外该 相同的细胞系将在裸鼠的乳腺脂肪垫中生长， 在体内比较自发转移的能力。

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.