SERM Regulation of PAK Pathway in Endometrial Cancer

描述（申请人提供）：子宫内膜癌是女性生殖道最常见的恶性肿瘤。目前公认的是，长期使用合成雌激素受体调节剂（SERM）如他莫昔芬与子宫内膜癌发病风险增加有关。除子宫内膜癌外，他莫昔芬的使用还与子宫内膜增厚、功能失调性子宫出血、子宫内膜息肉、子宫内膜增生和子宫肉瘤有关。尽管关于SERM临床应用的信息显著增长，但在了解SERM的细胞靶点调节子宫内膜癌发生的机制方面仍未取得进展。如下所述，我们最近的工作表明，刺激p21活化激酶（Pak1），一种丝氨酸/苏氨酸信号激酶，在细胞运动、侵袭性和存活中起着重要作用，所有这些都是肿瘤进展所必需的(7)。我们的前期研究发现SERM刺激Pak1的表达和活性，动力蛋白轻链1 （dynein light chain 1, DLC1）是Pak1的生理靶点，Pak1-DLC1通路可能参与了子宫内膜癌的分子发病机制。本研究拟探讨Pak1和DLC1参与SERM暴露后子宫内膜癌细胞雌激素受体（ER）功能和致瘤表型调控的分子机制。

DESCRIPTION (provided by applicant): Endometrial cancer is the most common malignancy of the female genital tract. It is now accepted that the long-term use of synthetic estrogen receptor modulators (SERM) such as tamoxifen are associated with an increased risk of developing endometrial cancer. In addition to endometrial cancer, tamoxifen use has also been associated with endometrial thickening, dysfunctional uterine bleeding, endometrial polyps, endometrial hyperplasia, and uterine sarcoma. Despite the remarkable growth of information about the clinical utility of SERM, the progress in understanding the mechanism by which cellular target(s) of SERMs modulate endometrial carcinogenesis remains elusive. As described below, our recent work suggests that stimulation of p21-activated kinase (Pak1), a serine/threonine signaling kinase, plays a significant role in cell motility, invasiveness and survival, all of which are required for tumor progression (7). Our preliminary studies have discovered that SERM stimulates the expression and activity of Pak1, that dynein light chain 1 (DLC1) is a physiological target of Pak1, and that the Pak1-DLC1 pathway may be involved in the molecular pathogenesis of endometrial cancer. Here we propose to investigate the molecular mechanism by which Pak1 and DLC1 participate in the regulation of estrogen receptor (ER) functions and tumorigenic phenotypes in endometrial cancer cells upon SERM exposure. Since hyperexpression of Pak1 and DLC1 may contribute to the development of aggressive phenotypes, dysfunction in the Pak1 pathway in the endometrium may constitute an important early step(s) in endometrial cancer development. Thus, our working hypotheses are "SERM-mediated deregulation of Pakl activity stimulates DL C phosphorylation and ER functions, and consequently, contributes to an enhanced cell survival, anchorage-independence, and progression of endometrial cancer cells; these phenotypic effects of Pakl might be controlled by ER phosphorylation by Pak1 and further potentiated by Pak1 modulation of DLC1-ER interaction". In addition, we will also delineate ER-independent tumorigenic functions of Pak1 and DLC1 in endometrial cancer cells. To address these hypotheses, our specific aims are to determine: (1) The biochemical basis and functional significance of SERM regulation of Pak1 in endometrial cancer cells; (2) The influence of DLC overexpression and Pak1 regulation of DLC1 functions on the phenotypic changes associated with the progression of endometrial cancer; (3) The influence of SERM on the functions of Pakl and DLC1, and on the biology endometrial tumorigenesis using the Pten heterozygous mice progression model; and (4) he expression characteristics and significance of Pak1 and DLC1 during multi-step endometrial cancer pathogenesis in humans. An innovative aspect of our proposal is the use of novel in vitro, in vivo transgenic models, and human endometrial tumors with follow-up data to gain new insight about the roles of Pak1 and DLC1 in the biology and tumorigenesis of endometrial cancer. These studies will uniquely define the mechanisms through which DLC1 and its upstream Pak1 kinase regulate survival, mitogenesis and tumorigenesis of endometrial cancer cells. Our proposed research is significant in that the knowledge gained from this research will enhance our understanding of the roles of newly identified cellular targets of SERM in the biology of endometrium. A better understanding of critical regulatory pathways with roles in cancer progression is likely to form the basis for new advances in identifying novel molecular targets, detecting, and treating endometrial cancer, by identifying Pak1-DLC as key regulatory signaling nodule in the action of SERM.