MECHANISMS OF AR-ER COLLABORATION IN HORMONE RESISTANCE AND METASTASIS OF BREAST CANCER

AR-ER 在乳腺癌激素抵抗和转移中的合作机制

基本信息

  • 批准号:
    10113551
  • 负责人:
  • 金额:
    $ 36.26万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-03-07 至 2023-02-28
  • 项目状态:
    已结题

项目摘要

Estrogen receptor (ER)-positive breast tumors are treated with endocrine therapies which specifically target the ER. Patients can remain disease-free for many years; however, resistance to treatment eventually develops, and the majority of women will suffer a recurrence of metastatic cancer. We hypothesized that the key to the long-term treatment of women with ER-positive breast cancers was to focus on identifying novel mechanisms of resistance using metastatic tumors resistant to therapy where tumor evolution and clonal selection have occurred. We identified the androgen receptor (AR) as a new clinical target which was up regulated in resistant, metastatic tumors. We have learned that AR functionally collaborates with ER, and that resistance may be associated with a failure of hormone therapy to completely block both androgen and estrogen signaling. We have also discovered that AR-overexpressing cells become metastatic in vivo. Furthermore, we were the first to identify that the estrogen receptor ESR1 gene can be mutated in metastatic tumors; acquiring hormone-independent and endocrine therapy-resistant functions which we hypothesize will also be impacted by ligand-independent AR signaling. Importantly, cells with ESR1 mutations also up-regulate AR, demonstrating a unique relationship between these mutations and AR. Our Aims are: (1) To determine if receptor crosstalk (WT or mutant ER with AR) is a mechanism of resistance to hormonal agents, (2) To determine whether AR employs novel nuclear receptor interactions to drive hormone resistance, and (3) To determine AR and ESR1 mutant effects on invasion and metastasis. Key success has been made in developing resistant models with endogenous up regulation of AR coincident with acquired resistance, and we have already identified potential AR-mediated candidate resistance mechanisms. Undoubtedly hormone therapy resistance in patients is multifactorial and will require combination hormonal and targeted therapy along with knowledge of the activation status of key pathways, such as those arising from mutations in ER in metastatic tumors. Our work will impact a large number of women with ER-positive breast cancer who recur with therapy-resistant disease.
雌激素受体(ER)阳性乳腺肿瘤的治疗与内分泌疗法,具体目标是 儿患者可以保持多年无病;然而,最终会出现对治疗的耐药性, 并且大多数妇女将遭受转移性癌症的复发。我们假设 ER阳性乳腺癌女性的长期治疗重点是确定新的机制 使用对治疗有抗性的转移性肿瘤来进行抗性的研究,其中肿瘤进化和克隆选择具有 发生了。我们将雄激素受体(AR)确定为一个新的临床靶点, 耐药的转移性肿瘤我们已经了解到AR在功能上与ER合作, 可能与激素治疗未能完全阻断雄激素和雌激素有关 信号我们还发现AR过表达细胞在体内具有转移性。而且我们 是第一个发现雌激素受体ESR 1基因可以在转移性肿瘤中突变的人; 我们假设非依赖性和内分泌治疗抵抗功能也会受到影响 通过配体非依赖性AR信号传导。重要的是,具有ESR 1突变的细胞也上调AR, 证明了这些突变和AR之间的独特关系。我们的目标是:(1)确定是否 受体串扰(WT或突变型ER与AR)是对激素药物的抗性机制,(2) 确定AR是否采用新的核受体相互作用来驱动激素抵抗,以及(3) 确定AR和ESR 1突变体对侵袭和转移的影响。在以下方面取得了重大成功: 开发具有与获得性抗性一致的AR内源上调的抗性模型,并且我们 已经确定了潜在的AR介导的候选耐药机制。无疑是荷尔蒙 患者的治疗抵抗是多因素的,需要激素和靶向治疗的组合 沿着对关键通路的激活状态的了解,例如由ER突变引起的那些, 转移性肿瘤我们的工作将影响大量复发的ER阳性乳腺癌妇女 治疗抵抗性疾病。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Suzanne AW Fuqua其他文献

Suzanne AW Fuqua的其他文献

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{{ truncateString('Suzanne AW Fuqua', 18)}}的其他基金

Translational Breast Cancer Research Training Program
转化乳腺癌研究培训计划
  • 批准号:
    10475088
  • 财政年份:
    2018
  • 资助金额:
    $ 36.26万
  • 项目类别:
Translational Breast Cancer Research Training Program
转化乳腺癌研究培训计划
  • 批准号:
    10249135
  • 财政年份:
    2018
  • 资助金额:
    $ 36.26万
  • 项目类别:
MECHANISMS OF AR-ER COLLABORATION IN HORMONE RESISTANCE AND METASTASIS OF BREAST CANCER
AR-ER 在乳腺癌激素抵抗和转移中的合作机制
  • 批准号:
    9884532
  • 财政年份:
    2017
  • 资助金额:
    $ 36.26万
  • 项目类别:
MECHANISMS OF AR-ER COLLABORATION IN HORMONE RESISTANCE AND METASTASIS OF BREAST CANCER
AR-ER 在乳腺癌激素抵抗和转移中的合作机制
  • 批准号:
    9316124
  • 财政年份:
    2017
  • 资助金额:
    $ 36.26万
  • 项目类别:
Career Enhancement Program (CEP)
职业提升计划(CEP)
  • 批准号:
    10460221
  • 财政年份:
    2014
  • 资助金额:
    $ 36.26万
  • 项目类别:
Career Enhancement Program (CEP)
职业提升计划(CEP)
  • 批准号:
    10704556
  • 财政年份:
    2014
  • 资助金额:
    $ 36.26万
  • 项目类别:
Career Enhancement Program (CEP)
职业提升计划(CEP)
  • 批准号:
    10219973
  • 财政年份:
    2014
  • 资助金额:
    $ 36.26万
  • 项目类别:
Nuclear Receptor, Transcription and Chromatin Biology Program
核受体、转录和染色质生物学项目
  • 批准号:
    10674560
  • 财政年份:
    2007
  • 资助金额:
    $ 36.26万
  • 项目类别:
Nuclear Receptor, Transcription and Chromatin Biology Program
核受体、转录和染色质生物学项目
  • 批准号:
    10439821
  • 财政年份:
    2007
  • 资助金额:
    $ 36.26万
  • 项目类别:
Cancer Research Career Enhancement and Related Activities
癌症研究职业提升及相关活动
  • 批准号:
    10239116
  • 财政年份:
    2007
  • 资助金额:
    $ 36.26万
  • 项目类别:

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