MAMMARY SIGNALING BY ENVIRONMENTAL AGENTS

超出所提供的空间。乳腺癌是一种主要的疾病和医疗保健问题，在美国，每九名妇女中就有一名受其影响。尽管过去几年在遗传风险因素方面有了重大发现，但据估计，遗传因素仅直接占所有乳腺癌病例的10%左右。环境和饮食因素可能在乳腺癌的病因学中起着重要作用，但我们还不知道哪些因素会增加女性患乳腺癌的风险，或者哪些因素可能是致病因素。环境和饮食因素可能与基因和基因产物相互作用，通过肿瘤的发生、促进和发展过程诱发女性乳腺癌。虽然对环境化学物质引发肿瘤的机制有很多研究，但对这些物质促进和进展肿瘤的机制的研究还不够。在这项先前资助的为期4年的资助的竞争性更新中，我们发现一类已知的（啮齿动物）乳腺癌致癌物，多环芳烃（PAHs，如苯并[a]芘，BaP），通过表皮生长因子受体（EGFR）模拟生长因子信号，导致乳腺上皮细胞增殖和存活增加。细胞增殖增加和细胞死亡抑制可能是导致乳腺癌的乳腺上皮细胞促进和进展的重要机制。PAHs（如BaP）通过三种不同的途径改变乳腺上皮细胞的信号通路，包括Ah受体的激活、Ca2+信号的增加和引起氧化应激。研究表明，细胞内Ca2+的调节可能在Ca2+依赖性和氧化应激相关途径（INK， Erk和p38 MAP激酶）的信号传导中起重要作用。在人乳腺上皮细胞（HMEC）和MCF-10A细胞的原代培养中，BaP增加细胞内Ca2+需要P450代谢，芳香烃受体（AhR）似乎在MCF-10A细胞的生长调节和凋亡保护中发挥关键作用。初步结果表明，氧化还原循环bap -醌（BPQs）通过氧化应激机制主要负责Ca2+升高。我们还发现，醛酮还原酶（AKR1C1）在MCF-10A细胞中表达，该酶的BaP产物7,8- bp -醌（7,8- bpq）在MCF-10A细胞中具有独特的Ca2+升高活性。7,8- bpq升高Ca2+的生化机制可能与ryanodine受体（RyR）活性有关，因为我们最近发现这些受体在MCF- 10A细胞中高度表达。这些研究将进一步明确AhR、Ca2+和氧化应激信号通路在MCF-10A细胞和正常人乳腺上皮细胞（HMEC）中促进乳腺肿瘤的潜在机制中的作用。这些研究的结果将有助于更好地确定环境多环芳烃在人类乳腺癌病因学中的作用。我/性能网站 ======================================== 节结束 ===========================================

EXCEED THE SPACE PROVIDED. Breast cancer is a major disease and health care concern that will affect one in every nine women in the U.S. Despite significant discoveries in the past few years concerning genetic risk factors, it is estimated that genetic factors only directly account for approximately 10% of all breast cancer cases. Environmental and dietary factors likelyplay a major role in the etiology of breast cancer, yet we do not yet know what agents increase a women's risk of breast cancer or may be causative agents. Environmental and dietary agents likely interact with genes and gene products to induce breast cancer in women through processes of tumor initiation, promotion, and progression. While there has been much work on mechanisms by which environmental chemicals produce tumor initiation, there has been inadequate work on mechanisms of tumor promotion and progression by these agents. In this competitive renewal of a previously funded 4 yr grant, we have found that a chemical class of known (rodent) mammary carcinogens, polycyclicaromatic hydrocarbons (PAHs, such as benzo[a]pyrene, BaP),mimic growth factor signaling through the epidermal growth factor receptor (EGFR) leading to increased mammary epithelial cell proliferation and survival. Increased cell proliferation and inhibition of cell death are likely important mechanisms of mammaryepithelial cell promotion and progression leading to breast cancer. There appear to be three different pathways by which PAHs, such as BaP alter signaling pathways in mammary epithelial cells, including activation of Ah receptors, increasing Ca2+signaling, and causing oxidative stress. Studies suggest that modulation of intracellular Ca2+ may play an important role in signaling Ca2+-dependent and oxidative stress associated pathways (INK, Erk, and p38 MAP kinases). P450 metabolism is required for BaP to increase intracellular Ca2+ in primary cultures of human mammary epithelial cells (HMEC) and MCF-10A cells, and the aromatic hydrocarbon receptor (AhR) appears to play a critical role in growth regulation and protection of MCF-10A cells from apoptosis. Initial results suggest that redox-cycling BaP-quinones (BPQs) are largely responsible for Ca2+ elevation via an oxidant stress mechanism. We have also discovered that an aldoketoreducatse (AKR1C1) is expressed in MCF-10A cells and that a BaP product of this enzyme, 7,8-BP-quinone (7,8-BPQ) has unique Ca2+-elevating activity in MCF-10A cells. The biochemical mechanism of Ca2+ elevation by 7,8-BPQ may be associated with ryanodine receptor (RyR) activity, as we have recently found that these receptors are highly expressed in MCF- 10A cells. These studies will further define the role of AhR, Ca2+, and oxidative stress signaling pathways in potential mechanisms of breast tumor promotion in MCF-10A cells and normal human mammary epithelial cells (HMEC). The results of these studies should help better define the role of environmental PAHs in the etiology of human breast cancer. I/PERFORMANCE SITE ========================================Section End===========================================