SRC-3/PELP1 complexes drive stem-like phenotypes in luminal breast cancer

SRC-3/PELP1 复合物驱动管腔乳腺癌中的干细胞样表型

基本信息

  • 批准号:
    10059182
  • 负责人:
  • 金额:
    $ 48.82万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-12-01 至 2024-11-30
  • 项目状态:
    已结题

项目摘要

Abstract Breast cancer recurrence remains a significant risk among node-positive patients. Breast cancer stem or stem- like cells (BCSCs herein) disseminate and evade first-line therapies, and account for high mortality among patients with advanced endocrine-resistant disease. The objective of this proposal is to define the signaling pathways that drive the emergence and expansion of endocrine-resistant BCSCs, with the goal of blocking epigenetic events to specifically target this population of tumor cells. Filling this knowledge gap will pave the way for intervention that blocks BCSCs and ensures long-term disease-free survival. We identified the chromatin- associated, steroid receptor (SR) transcriptional coregulator, PELP1, as a mediator of BCSC expansion. Utilizing mass spectrometry, we identified the steroid receptor coactivator-3, SRC-3 (also known as AIB1), as a novel and preferential interactor with cytoplasmic relative to nuclear PELP1. Notably, PELP1 increased activation of SRC-3 in BC cells, while SRC-3 knockdown blocked PELP1-induced BCSC expansion, suggesting an essential role for active PELP1/SRC3 complexes in BCSC outgrowth. In follow-up studies, we found that cytoplasmic PELP1 promotes the phosphorylation of SRC-3 on Thr24 and Ser857. Work of others has implicated SRC-3 pSer857 in breast cancer metastasis as a key substrate of the bifunctional kinase/phosphatase known as PFKFB4. In related work, we showed that PELP1 forms constitutive transcriptional complexes with both estrogen (ER) and progesterone (PR) receptors in breast cancer models and patient tumors; a scaffolding action of PR- B, but not progesterone, was required for ER phosphorylation and regulation of genes by ER/PR/PELP1 complexes, including gene sets important for tamoxifen resistance. Herein, we hypothesize that ER/PR/PELP1/SRC-3 complexes recruit and amplify key cytoplasmic signaling pathways that mediate epigenetic events required for chromatin remodeling and reprogramming of steroid receptor (SR)-regulated transcriptomes required for expansion of therapy resistant BCSC populations. We will test this hypothesis in breast cancer models and in the following Specific Aims: • Identify PELP1/SRC-3-activated signaling pathways essential for BCSC expansion and therapy resistance. • Determine how PELP1/SRC-3 complexes reprogram SR transcriptomes. • Determine if PELP1/SRC-3/SR cooperation promotes tumorigenesis in vivo. Current therapies primarily inhibit BC proliferation, but fail to adequately target BCSCs. Understanding the mechanisms of PELP1/SRC-3/SR signaling and reversible epigenetic regulation of BCSCs will reveal novel therapies that target the required components of this complex (i.e. other than ER) or downstream signaling molecules and prevent or reverse this process, thus significantly impacting on the longevity of patients with metastatic breast cancer.
摘要

项目成果

期刊论文数量(0)
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Carol A Lange其他文献

Carol A Lange的其他文献

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{{ truncateString('Carol A Lange', 18)}}的其他基金

Progesterone Receptor (PR) Signaling Cross Talk Drives ER+ Breast Cancer
黄体酮受体 (PR) 信号串扰导致 ER 乳腺癌
  • 批准号:
    10330474
  • 财政年份:
    2020
  • 资助金额:
    $ 48.82万
  • 项目类别:
Progesterone Receptor (PR) Signaling Cross Talk Drives ER+ Breast Cancer
黄体酮受体 (PR) 信号串扰导致 ER 乳腺癌
  • 批准号:
    9884201
  • 财政年份:
    2020
  • 资助金额:
    $ 48.82万
  • 项目类别:
Progesterone Receptor (PR) Signaling Cross Talk Drives ER+ Breast Cancer
黄体酮受体 (PR) 信号串扰导致 ER 乳腺癌
  • 批准号:
    10593962
  • 财政年份:
    2020
  • 资助金额:
    $ 48.82万
  • 项目类别:
SRC-3/PELP1 complexes drive stem-like phenotypes in luminal breast cancer
SRC-3/PELP1 复合物驱动管腔乳腺癌中的干细胞样表型
  • 批准号:
    10532137
  • 财政年份:
    2019
  • 资助金额:
    $ 48.82万
  • 项目类别:
SRC-3/PELP1 complexes drive stem-like phenotypes in luminal breast cancer
SRC-3/PELP1 复合物驱动管腔乳腺癌中的干细胞样表型
  • 批准号:
    9884189
  • 财政年份:
    2019
  • 资助金额:
    $ 48.82万
  • 项目类别:
SRC-3/PELP1 complexes drive stem-like phenotypes in luminal breast cancer
SRC-3/PELP1 复合物驱动管腔乳腺癌中的干细胞样表型
  • 批准号:
    10295759
  • 财政年份:
    2019
  • 资助金额:
    $ 48.82万
  • 项目类别:
Inducible PTK6 expression drives oncogenic signaling in breast cancer
诱导性 PTK6 表达驱动乳腺癌中的致癌信号传导
  • 批准号:
    9762021
  • 财政年份:
    2015
  • 资助金额:
    $ 48.82万
  • 项目类别:
Inducible PTK6 expression drives oncogenic signaling in breast cancer
诱导性 PTK6 表达驱动乳腺癌中的致癌信号传导
  • 批准号:
    9148251
  • 财政年份:
    2015
  • 资助金额:
    $ 48.82万
  • 项目类别:
Inducible PTK6 expression drives oncogenic signaling in breast cancer
诱导性 PTK6 表达驱动乳腺癌中的致癌信号传导
  • 批准号:
    8985870
  • 财政年份:
    2015
  • 资助金额:
    $ 48.82万
  • 项目类别:
Role of Phospho-Progesterone Receptors (PR) in Hormone Refractory Breast Cancer
磷酸孕酮受体 (PR) 在激素难治性乳腺癌中的作用
  • 批准号:
    8623286
  • 财政年份:
    2013
  • 资助金额:
    $ 48.82万
  • 项目类别:

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