Targeting AP-1 / ER Crosstalk for the Prevention and Treatment of Breast Cancer

靶向 AP-1/ER 串扰预防和治疗乳腺癌

• 批准号: 7580985
• 负责人: POWEL H BROWN
• 金额: $ 28.5万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-06 至 2009-09-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7580985
• 关键词: Affect; Apoptosis; Aromatase Inhibitors; Binding; Biochemical; Biological Markers; Breast; Breast Cancer Cell; Breast Cancer Prevention; Breast Cancer Treatment; Cancer Cell Growth; Cells; Collaborations; Development; ERBB2 gene; Estrogen Antagonists; Estrogen Receptor 1; Estrogen Receptors; Estrogen receptor negative; Estrogen receptor positive; Estrogens; Family; Foundations; Gene Expression; Genes; Growth; Growth and Development function; Health Benefit; Hormonal; Malignant - descriptor; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Molecular; Mus; NCOA3 gene; Oncogenes; Oncogenic; Partner in relationship; Pathway interactions; Pharmaceutical Preparations; Phosphotransferases; Prevention; Proteins; Public Health; Regulator Genes; Response Elements; Signal Transduction; Techniques; Testing; Tissues; Transcription Factor AP-1; Transgenic Mice; Woman; c-myc Genes; cell growth; cell transformation; chemotherapy; chromatin immunoprecipitation; hormone therapy; in vivo; inhibitor/antagonist; malignant breast neoplasm; mouse model; outcome forecast; overexpression; prevent; promoter; response; transcription factor; tumor

DESCRIPTION (provided by applicant): Estrogen is a critical regulator of breast growth, development, and transformation, and blocking estrogen- induced activation of the estrogen receptor (ER) has been the most successful way to treat and prevent breast cancer. However, despite the impressive activity of anti-estrogen and aromatase inhibitor drugs, currently available hormonal agents are unable to cure or prevent breast cancer in all women. We propose that through a better understanding of the molecules that participate with estrogen in regulating breast cell growth and transformation, it will be possible to develop molecularly targeted agents to more effectively prevent and treat breast cancer. Although the estrogen receptors have been well described, the molecular mechanism by which estrogen regulates breast cell growth and transformation is not fully understood. The "classical" pathway by which estrogen and the estrogen receptors activate gene expression is well known. However, recent studies have demonstrated that estrogen also regulates growth through other "non-classical" pathways by activating cytoplasmic kinase cascades and other transcription factors through transcription factor crosstalk. We and others have shown that a primary factor activated by estrogen is the AP-1 transcription factor, a critical regulator of breast cell growth and invasion and a marker of poor prognosis in women with breast cancer. We now hypothesize that the crosstalk between estrogen receptors and AP-1 transcription factors is essential for breast cell growth and transformation, and that this pathway can be targeted for the prevention and treatment of breast cancer. We propose to investigate how activation of the AP-1 transcription factor by estrogen controls expression of estrogen-regulated genes, mammary tumor development, and breast cancer growth. Specifically, we will: (1) investigate the molecular mechanism by which ER and AP-1 proteins collaborate to induce expression of critical growth regulatory genes in breast cells; (2) determine whether in vivo AP-1 blockade prevents oncogene-induced breast cancer; and (3) determine whether inhibition of the AP-1 transcription factor will suppress the growth of established breast cancers and enhance the effect of hormonal- and chemo-therapies. These studies will have a major public health benefit by providing the foundation and rationale to develop agents capable of disrupting this collaboration between AP-1 and ER, thus effectively preventing all breast cancers.

描述（由申请人提供）：雌激素是乳房生长，发育和转化的关键调节剂，以及阻止雌激素诱导的雌激素受体（ER）的激活是治疗和预防乳腺癌的最成功方法。然而，尽管抗雌激素和芳香酶抑制剂的活性令人印象深刻，但目前可用的激素剂仍无法治愈或预防所有女性的乳腺癌。我们建议，通过更好地理解参与雌激素来调节乳腺细胞生长和转化的分子，可以开发出分子靶向剂以更有效地预防和治疗乳腺癌。尽管已经很好地描述了雌激素受体，但雌激素调节乳腺细胞生长和转化的分子机制尚未完全了解。雌激素和雌激素受体激活基因表达的“经典”途径是众所周知的。然而，最近的研究表明，雌激素还通过其他“非古典”途径来调节生长，通过激活细胞质激酶级联反应和其他转录因子通过转录因子串扰来调节生长。我们和其他人表明，雌激素激活的主要因素是AP-1转录因子，这是乳腺细胞生长和侵袭的关键调节剂，也是乳腺癌女性预后不良的标志。现在，我们假设雌激素受体和AP-1转录因子之间的串扰对于乳腺细胞的生长和转化至关重要，并且该途径可以针对预防和治疗乳腺癌。我们建议通过雌激素控制AP-1转录因子的激活如何控制雌激素调节的基因的表达，乳腺肿瘤发育和乳腺癌的生长。具体而言，我们将：（1）研究ER和AP-1蛋白合作以诱导乳腺细胞中关键生长调节基因表达的分子机制； （2）确定体内AP-1阻滞是否可以防止癌基因诱导的乳腺癌； （3）确定抑制AP-1转录因子是否会抑制已建立的乳腺癌的生长，并增强激素和化学性治疗的作用。这些研究将通过提供基金会和理由来开发能够破坏AP-1和ER之间这种合作的代理人，从而有效防止所有乳腺癌。