ALKYL PCDFS--INHIBITION OF MAMMARY CANCER

乳腺癌和子宫内膜癌是北美妇女过早死亡的主要原因之一。在这个国家，大约九分之一的妇女在一生中会患上乳腺癌，乳腺癌的发病率一直在上升。全世界每年诊断出超过15万例新的子宫内膜癌病例。流行病学研究清楚地表明，乳腺癌和子宫内膜癌有一系列共同的风险因素，包括：初潮年龄早、更年期年龄晚、肥胖、产次和无对抗性雌激素暴露增加。 高比例的早期乳腺肿瘤是雌激素受体阳性（ER+），并且这些患者中的许多对抗雌激素或用药物如他莫昔芬的内分泌疗法有反应，他莫昔芬现在已成功地用于治疗数百万患有乳腺癌的妇女。不幸的是，对他莫昔芬的耐药性可以在一些患者中发展，现在越来越多的人担心长期使用这种药物会增加子宫内膜癌的风险。因此，迫切需要开发可单独使用或与他莫昔芬联合治疗（例如与他莫昔芬）用于治疗肿瘤依赖性肿瘤的新药。 我们的研究已经确定了替代取代的烷基PCDFs作为一种新的机制为基础的类抗雌激素，阻断雌激素诱导的乳腺和子宫内膜细胞/肿瘤的生长，通过ER和Ah受体信号通路之间的串扰。根据以往研究的结果，将在DMBA诱导的大鼠乳腺肿瘤模型（目标1）和携带乳腺癌细胞异种移植物的无胸腺裸鼠（目标2）中彻底研究选定的烷基多氯二苯并呋喃的抗肿瘤活性。 目标3将侧重于它们在啮齿动物模型中对子宫内膜癌生长的抑制作用，目标4将确定他莫昔芬和烷基多氯二苯并呋喃在乳腺癌和子宫内膜癌模型中的重要相互作用。 这些研究还将确定烷基多氯二苯并呋喃对他莫昔芬诱导的子宫、骨骼雌激素反应的组织特异性抑制作用以及对血清胆固醇水平的抑制作用。 初步研究表明，烷基多氯二苯并呋喃仅在子宫内阻断他莫昔芬的作用。 因此，拟议的研究将定义一类新的基于机制的抗雌激素药物，可单独使用或与他莫昔芬联合使用，用于治疗乳腺癌和子宫内膜癌。

Mammary and endometrial cancer are among the leading causes of premature death in North American women. Approximately one in nine women in this country will develop breast cancer during their lifetime and the incidence of mammary cancer has been increasing. Over 150,000 new cases of endometrial cancer are diagnosed worldwide each year. Epidemiology studies have clearly demonstrated that both mammary and endometrial cancer share a common set of risk factors including: early age at menarche, late age at menopause, obesity, parity and increased exposure to unopposed estrogen. A high percentage of early stage mammary tumors are estrogen receptor positive (ER+), and many of these patients respond to antiestrogen or endocrine therapy with drugs such as tamoxifen which has now been successfully used for treatment of several million women with breast cancer. Unfortunately, resistance to tamoxifen can develop in some patients and there is now increasing concern that long term use of this drug increases the risk for endometrial cancer. Therefore, it is imperative to develop new drugs which can be used alone or in combination therapy (e.g. with tamoxifen) for treatment of hormone-dependent tumors. Our studies have identified alternate-substituted alkyl PCDFs as a new mechanism-based class of antiestrogens which block estrogen-induced mammary and endometrial cell/tumor growth via crosstalk between the ER and Ah receptor signaling pathways. Based on results of previous studies, the antitumorigenic activities of selected alkyl PCDFs will be thoroughly investigated in the DMBA-induced rat mammary tumor model (Aim 1) and athymic nude mice bearing breast cancer cell xenografts (Aim 2). Aim 3 will focus on their inhibition of endometrial cancer growth in rodent models and Aim 4 will determine the important interaction of tamoxifen and alkyl PCDFs in both mammary and endometrial cancer models. These studies will also determine tissue-specific inhibition of tamoxifen-induced estrogenic responses in the uterus, bone and on serum cholesterol levels by alkyl PCDFs. Preliminary studies indicate that alkyl PCDFs block the effects of tamoxifen only in the uterus. Thus the proposed studies will define a new mechanism-based class of antiestrogens that can be used alone or in combination with tamoxifen for treatment of breast and endometrial cancer.