PREVENTION OF BREAST CANCER USING SELECTIVE RETINOIDS

类维A酸类化合物在动物和人类中都是很有前途的化学预防药物。 然而，由于目前可用的维甲酸类化合物相对有毒， 维甲酸一般不用于癌症预防。长期的 我们研究的目标是阐明维甲酸的作用机制 抑制致癌，以开发更有效和毒性更低的产品 化学防护剂。我们的初步研究表明，9cra 抑制转基因小鼠的乳腺肿瘤发展，但这是 也会产生明显的毒性。我们还展示了这条途径- 选择性类维甲酸，毒性可能比自然产生的要小 广谱维甲酸，可抑制正常和 恶性乳腺细胞。我们现在建议检验以下假设 特定途径的维甲酸将有效预防乳房 降低毒性的致癌作用。首先，我们将确定 维甲酸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)对不同类型肿瘤的化学预防作用 通过不同机制发展成乳腺肿瘤的动物模型， 例如通过c-myc或Her2/neu基因的过度表达，或通过慢性 雌激素暴露。我们还将确定这个广谱 维甲酸干扰癌前病变向恶性病变的进展 这些模型中的乳腺肿瘤。其次，我们将确定哪一个 途径选择性的维甲酸类化合物能够抑制体内的癌症发生。 我们将比较RAR-，RXR-， 抗AP-1选择性维甲酸与9cRA在动物中的作用 9cRA可预防乳腺癌的发生。第三，我们将确定是否 与生长相关的维甲酸调节基因表达的变化 调节与维甲酸成功的化学预防有关。 我们将研究维甲酸诱导的蛋白表达的变化。 RARbeta、E-钙粘附素和基质金属蛋白酶-9，所有这些都是 参与调节乳腺细胞的生长和侵袭性。我们 将确定这些标志物的表达是否发生变化 与增殖减少、细胞凋亡增加或 减少了侵入性。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维甲酸 毒性最小的肿瘤形成。这样的调查将提供 开发更具体的预防性维甲酸的基础 以及在临床上测试这类药物的合理性 在人体上进行化学预防试验。

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.