INDUCTION OF APOPTOSIS IN BREAST CANCER

丰塔纳研究小组已经鉴定出一种类视色素6-[3-1-金刚烷基]-4- 羟苯基]-2-萘羧酸（AHPN）， 维甲酸耐药者细胞G1期阻滞及随后的细胞凋亡 乳腺癌细胞通过视黄酸核受体非依赖性 通路 AHPN还可诱导乳腺癌细胞凋亡 缺乏功能性p53并对生长抑制有抗性的细胞系 类维生素A。 因此，鉴定缺乏的AHPN类似物， 类维生素A的毒副作用，因为它们不能结合 类维生素A受体将提供新的治疗药物， 浸润性乳腺癌 乳腺癌细胞凋亡研究 首先进行调查，以确定机制， AHPN抑制乳腺癌细胞的生长和凋亡， 可以更容易地鉴定AHPN的改进类似物， 检查这些类似物调节乳腺癌的能力， 生长和凋亡，以确定用于治疗的最佳类似物 的乳腺癌和证实AHPN的作用机制。 具体目标AHPN的功能独立于类维生素A 受体诱导G1期阻滞和细胞凋亡，通过一个独特的 机制 将进行研究，以确定这是否 机制是（A）与细胞内受体结合（B）增强 gadd 45启动子转录通过激活一个反式 元素，或~稳定WAF-1，通过AHPN- 在其3 '非翻译区的应答元件。 具体目标 将评价显示增强疗效的AHPN类似物， 它们诱导G1期阻滞和细胞凋亡的能力，增强WAF-1 表达，下调bcl-XL表达，并增强 化疗诱导的细胞凋亡。 具体目标 AHPN 道森实验室的类似物， 有效性（在低于或低于 与AHPN相当，但缺乏对类维生素A受体的亲和力， 因此将降低全身毒性）将评估其 调节人乳腺器官培养中细胞凋亡的能力 癌 Zhang实验室发现的有前途的类维生素A 将单独评价或与化疗药物联合评价 试剂或干扰素。 具体目标 最佳三 将评估AHPN类似物、类维生素A或类维生素A组合 因为它们能够诱导细胞凋亡并抑制人 SCID小鼠中的乳腺癌异种移植物。

The Fontana group has identified a retinoid 6-[3-1-adamantyl)-4- hydroxyphenyl]-2-naphthalene-carboxylic acid (AHPN) that induces G1 arrest and subsequent apoptosis in retinoid-resistant human breast carcinoma cells by a retinoid nuclear receptor-independent pathway. Moreover AHPN induced apoptosis in breast cancer cell lines lacking a functional p53 and resistant to growth inhibition of retinoids. Therefore, identification of analogs of AHPN that lack the toxic side effects of retinoids because of their inability to bind to retinoid receptors would offer new therapeutic agents against invasive breast cancer. Project Apoptosis in Breast Cancer will first conduct an investigation to define the mechanism by which AHPN inhibits growth and apoptosis in breast cancer cells, so that improved analogs of AHPN can be more readily identified, then examine the ability of these analogs to modulate breast cancer growth and apoptosis to identify the optimum analogs for treatment of breast cancer and substantiate the mechanism of AHPN action. Specific Aim IV.1. AHPN functions independently of the retinoid receptors to induce G1 arrest and apoptosis through a unique mechanism. Studies will be conducted to determine if this mechanism is (A) binding to an intracellular receptor (B) enhancing gadd 45 promoter transcription through the activation of a trans element, or ~ stabilizing WAF-1 , message through an AHPN- responsive element in its 3'untranslated region. Specific Aim IV.2. AHPN analogs that display enhanced efficacy will be evaluated for their ability to induce G1 arrest and apoptosis, enhance WAF-1 expression, downregulate bcl-XL expression, and enhance chemotherapy-induced apoptosis. Specific Aim IV.3. The AHPN analogs from the Dawson laboratory that display the greatest efficacy (induce apoptosis at concentrations lower than or comparable to AHPN but lack affinity for the retinoid receptors and so will have reduced systemic toxicity) will be assessed for their ability to modulate apoptosis in organ culture of human breast carcinomas. Promising retinoids identified in the Zhang laboratory will be evaluated alone or in combination with chemotherapeutic agents or interferon. Specific Aim IV.4. The optimum three AHPN analogs, retinoids, or retinoid combinations will be assessed for their ability to induce apoptosis and inhibit the growth of human breast carcinoma xenografts in SCID mice.