MAMMARY TUMOR CHEMOPREVENTION BY ANGIOGENIC INHIBITORS

本研究的目的是确定血管生成抑制剂是否可以作为高危女性乳腺癌的化疗药物。 我们的假设是：导致浸润前乳腺疾病的遗传和表观遗传事件也导致血管生成表型;浸润前乳腺疾病进展为晚期形式依赖于血管生成;阻断血管生成可防止浸润前肿瘤的发展，抑制进展到下一阶段，并最终防止浸润性疾病。 对于这些研究，我们将使用两种充分表征的模型来形成浸润前和浸润性乳腺肿瘤，即7，12-二甲基苯并[a]蒽（DMBA）和N-亚硝基-N-甲基脲（NMU）诱导的大鼠乳腺肿瘤。 我们的具体目标是研究致癌物诱导的浸润前乳腺肿瘤成为血管生成的时间框架，即抑制血管生成可以防止致癌物诱导的浸润前和浸润性乳腺肿瘤的形成和进展，这与特定的遗传或表观遗传致癌途径无关，并且抑制血管生成将增强雌激素受体阻断剂的化学预防作用。两种血管生成抑制剂将在长期给予时进行测试，从致癌物暴露时开始，并在一个月延迟后，以允许在治疗前形成浸润前肿瘤。 将检查肿瘤发展不同阶段的组织的表型变化，如组织形态学和血管分布程度。 此外，将在体外和体内血管生成试验中检测其血管生成潜力。最后，将检查它们的遗传变化，特别是DNA加合物的数量和类型以及密码子61处的H-ras突变。 这项研究是独特的，通过检查血管生成在浸润前肿瘤中的作用，这是一个很大程度上未探索的领域。 此外，这项研究提出了一种非激素的方法来解决高危妇女的化学预防问题。

The goal of this research is to determine whether inhibitors of angiogenesis can serve as chemoprophylactics for breast cancer in high risk women. Our hypothesis is that: the genetic and epigenetic events which lead to pre-invasive breast disease also lead to an angiogenic phenotype; progression to advanced forms of pre-invasive breast disease is dependent upon angiogenesis; and blocking angiogenesis prevents the development of pre-invasive tumors, inhibits progression to the next stage and ultimately prevents invasive disease. For these studies we shall use two well-characterized models for the formation of pre-invasive and invasive mammary tumors, the 7,12-dimethylbenz[a]anthracene (DMBA) and N-nitroso-N-methylurea (NMU) - induced rat mammary tumors. Our specific aims are to investigate the time frame in which carcinogen-induced pre-invasive mammary tumors become angiogenic, that inhibition of angiogenesis prevents the formation and progression of carcinogen-induced pre-invasive and invasive breast tumors, that this occurs independent of the specific genetic or epigenetic pathway of carcinogenesis, and that inhibition of angiogenesis will potentiate the chemopreventive effects of estrogen receptor blocking agents. Two angiogenic inhibitors will be tested when given chronically, beginning at the time of carcinogen exposure, and after a one-month delay, to allow pre-invasive tumors to form prior to treatment. Tissues at different stages of tumor development will be examined for phenotypic changes such as histomorphology and degree of vascularity. In addition, they will be tested for angiogenic potential in angiogenic assays in vitro and in vivo. Finally, they will be examined for genetic changes, specifically the number and type of DNA-adducts and H-ras mutations at codon 61. This study is unique by examining the role of angiogenesis in pre-invasive tumors, an area that is largely unexplored. In addition, this study presents a non-hormonal approach to the problem of chemoprophylaxis in high-risk women.