PREVENTION OF BREAST CANCER USING SELECTIVE RETINOIDS

类维生素A在动物和人类中是有前途的化学预防剂。 然而，由于目前可用的类维生素A相对有毒， 类维生素A通常不用于癌症预防。 长期 我们研究的目的是阐明维甲酸类化合物 抑制致癌作用，以开发更有效和毒性更小的 化学预防剂我们的初步研究表明9cRA 抑制转基因小鼠乳腺肿瘤的发展，但这是 也引起显著的毒性。 我们也发现了这条途径- 选择性类维生素A，其毒性可能低于天然存在的 广谱维甲酸，可抑制正常和 恶性乳腺细胞 我们现在提出检验以下假设： 途径特异性维甲酸将有效地防止乳腺癌 致癌作用，毒性降低。 首先，我们将确定 类维生素A抑制乳腺肿瘤发生的能力是否 依赖于特定的致癌途径。 我们将比较 9-顺式维甲酸（9cRA）在不同肿瘤中的化学预防作用 通过不同的机制发展乳腺肿瘤的动物模型， 例如通过c-myc或Her2/neu基因的过表达，或通过慢性 雌激素暴露 我们还将确定这种广谱 类维生素A干扰癌前病变向恶性进展 乳腺肿瘤的模型。 其次，我们将确定 途径选择性类维生素A能够抑制体内的致癌作用。 我们将比较RAR-，RXR-， 和抗AP-1-选择性类维生素A与9cRA的动物中， 9cRA预防乳腺癌的发生。第三，我们将确定 参与生长的类维生素A调节基因表达的变化 调节与类维生素A的成功化学预防有关。 我们将研究类维生素A诱导的表达的变化， RAR β，E-钙粘蛋白和基质金属蛋白酶-9，所有这些都是 参与调节乳腺细胞的生长和侵袭。 我们 然后将确定这些标志物表达的变化 与增殖减少、凋亡增加或 降低侵略性。 通过这些研究，我们计划确定 有效预防乳腺癌的途径选择性类维生素A 以最小的毒性抑制肿瘤发生。这些调查将提供 为开发更具体的预防性类维生素A奠定了基础 以及在临床中测试此类试剂的理由 在人体内进行的化学预防试验。

Retinoids are promising chemopreventive agents in animals and in humans. However, because currently available retinoids are relatively toxic, retinoids are not generally used for cancer prevention. The long-term goal of our studies is to elucidate the mechanisms by which retinoids inhibit carcinogenesis in order to develop more effective and less toxic chemopreventive agents. Our preliminary studies demonstrate that 9cRA suppresses mammary tumor development in transgenic mice, but that is also induces significant toxicity. We have also shown that pathway- selective retinoids, which may be less toxic than naturally occurring broad spectrum retinoids, can inhibit the proliferation of normal and malignant breast cells. We now propose to test the hypotheses that pathway-specific retinoids will efficiently prevent breast carcinogenesis with reduced toxicity. Firstly, we will determine whether the ability of retinoids to suppress breast tumorigenesis is dependent on the specific oncogenic pathway. We will compare the chemopreventive efficacy of 9-cis retinoic acid (9cRA) in different animal models which develop breast tumors through distinct mechanisms, such as by overexpression of the c-myc or Her2/neu genes, or by chronic estrogen exposure. We will also determine whether this broad-spectrum retinoid interferes with the progression of premalignant to malignant breast tumors in these models. Secondly, we will determine which pathway-selective retinoids are able to suppress carcinogenesis in vivo. We will compare the chemopreventive efficacy and toxicity of RAR-, RXR-, and anti-AP-1-selective retinoids with that of 9cRA in animals in which 9cRA prevents breast carcinogenesis. Thirdly, we will determine whether changes in the expression of retinoid-regulated genes involved in growth regulation are associated with successful chemoprevention by retinoids. We will investigate the retinoid-induced changes in the expression of RARbeta, E-cadherin and matrix metalloproteinase-9, all of which are involved in regulating the growth and invasiveness of breast cells. We will then determine whether changes in the expression of these markers are associated with decreased proliferation, increased apoptosis, or decreased invasiveness. Through these studies we plan to identify pathway-selective retinoids which effectively prevent mammary tumorigenesis with minimal toxicity. Such investigations will provide the foundation for the development of more specific preventive retinoids and the justification for testing such agents in clinical chemoprevention trials in humans.