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

说明(申请人提供)：雌激素是乳房生长、发育和转化的关键调节因子，阻断雌激素诱导的雌激素受体(ER)激活已成为治疗和预防乳腺癌最成功的方法。然而，尽管抗雌激素和芳香酶抑制剂药物的活性令人印象深刻，但目前可用的激素剂无法治愈或预防所有女性的乳腺癌。我们认为，通过更好地了解参与雌激素调节乳腺细胞生长和转化的分子，将有可能开发分子靶向药物来更有效地预防和治疗乳腺癌。虽然雌激素受体已经得到了很好的描述，但雌激素调节乳腺细胞生长和转化的分子机制还不完全清楚。众所周知，雌激素和雌激素受体激活基因表达的“经典”途径。然而，最近的研究表明，雌激素还通过其他非经典途径通过转录因子串扰激活细胞质激酶级联和其他转录因子来调节生长。我们和其他人已经证明，雌激素激活的一个主要因素是AP-1转录因子，它是乳房细胞生长和侵袭的关键调节因子，也是乳腺癌女性预后不良的标志。我们现在假设雌激素受体和AP-1转录因子之间的串扰对乳腺细胞的生长和转化是必不可少的，这一途径可以作为预防和治疗乳腺癌的靶点。我们建议研究雌激素激活AP-1转录因子如何控制雌激素调节基因的表达、乳腺肿瘤的发生和乳腺癌的生长。具体地说，我们将：(1)研究ER和AP-1蛋白协同诱导乳腺细胞关键生长调控基因表达的分子机制；(2)确定在体内阻断AP-1是否可以防止癌基因诱导的乳腺癌；以及(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，并增强激素和化疗的效果。这些研究将为开发能够破坏AP-1和ER之间的这种合作的药物提供基础和理论基础，从而有效地预防所有乳腺癌，从而对公众健康产生重大好处。

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.