Protein Kinase C Signaling and Breast Cancer

乳腺癌是女性癌症死亡的主要原因。抗雌激素药物，如他莫昔芬 ()，是有效的治疗雌激素受体阿尔法(ER)阳性的乳腺肿瘤通过延缓 抑制肿瘤生长，防止疾病复发，且副作用相对较少。然而， 几乎所有有反应性的肿瘤最终都会产生对TARN的耐药性。负责的机制(S) 的抵抗力和/或促生长作用目前尚不清楚。来自我们小组的研究和 另有研究表明，雌激素诱导的MARK激活(ERK1&2)主要由HRG/HER-1介导。 2/PKC-Delta/RAS通路。我们最近显示：(A)四分之三的抗雌激素药物具有抗药性 细胞株过表达总的和激活的PKC-Delta，(B)在TARN敏感的MCF中过表达PKC-Delta 7细胞在体内外均对耐药；(C)转铁蛋白或小干扰RNA抑制PKC-Delta 显著逆转抗雌激素耐药性，(D)先用rotlerin预处理细胞，然后再用TRAIL 与敏感细胞相比，体外抗雌激素耐药细胞的凋亡显著增加，(E) 在MCF7肿瘤中，TARN耐药肿瘤中PKC-Delta水平高于敏感肿瘤 异种移植，(F)免疫组织化学染色显示对Tarn耐药的人乳腺肿瘤 与敏感肿瘤相比，PKC-Delta水平升高。基于上述结果，我们 假设PKC-Delta的过度表达和/或激活在调节 雌激素受体阳性乳腺肿瘤细胞对雌激素的抗药性。我们提出了以下四个具体目标 为了验证我们的假设：目标1.我们将确定PKC-Delta的分子机制 过表达和/或激活抑制抗雌激素耐药细胞系的凋亡。目标2.我们将 研究PKC-Delta和/或其下游信号分子如何调节抗雌激素抵抗。目标 3.我们将确定PKC-Delta抑制剂使抗雌激素抵抗细胞对 TRAIL诱导细胞凋亡。目标4。我们将制定治疗策略，将体外观察转化为 活体内实用的治疗方法。我们预计拟议的调查将揭示出新的 对PKC-Delta调节抗雌激素耐药性的机制的洞察和数据应该 为今后乳腺癌的临床干预提供明确的分子靶点(S)。

Breast cancer is a leading cause of cancer death among women. Antiestrogen drugs, such as tamoxifen (Tam), are effective in the treatment of estrogen receptor alpha (ER)- positive breast tumors by slowing the growth of the tumors, preventing the recurrence of the disease, and with relatively few side effects. However, almost all responsive tumors eventually develop of Tarn-resistance. The mechanism(s) responsible for resistance and/or growth promoting effects of Tam are not clear at present. Studies from our group and others indicated estrogen-induced MARK activation (Erk1&2) is predominantly mediated by HRG/HER- 2/PKC-delta/Ras pathway. We have recently shown the following: (a) Three out of four antiestrogen resistant cell lines overexpress total and activated PKC-delta, (b) Overexpression of PKC-delta in Tarn-sensitive MCF- 7 cells leads to Tam-resistance both in vitro and in vivo, (c) Inhibition of PKC-delta by rottlerin or siRNA significantly reversed antiestrogen resistance, (d) Pretreatment of cells with rottlerin followed by TRAIL significantly enhanced apoptosis in antiestrogen resistant cells compared with sensitive cells in vitro, (e) PKC-delta levels are higher in Tarn-resistant tumors compared to Tam-sensitive tumors in MCF-7 tumor xenograft, (f) Immunohistochemical staining of Tarn-resistant human breast tumors showed a significant increase of PKC-delta levels compared with those in Tam-sensitive tumors. Based on the above results, we hypothesize that overexpression and/or activation of PKC-delta plays a major role in the regulation of antiestrogen resistance in ER-positive breast tumor cells. We are proposing the following four specific aims to test our hypotheses: Aim 1. We will determine the molecular mechanism by which PKC-delta overexpression and/or activation suppresses apoptosis in antiestrogen resistant cell lines. Aim 2. We will investigate how PKC-delta and/or its down stream signaling molecules regulate antiestrogen resistance. Aim 3. We will determine mechanism by which PKC-delta inhibitors) sensitizes antiestrogen resistant cells to TRAIL- induced apoptosis. Aim 4. We will develop treatment strategies to translate in vitro observations into practically applicable therapies in vivo. We anticipate that the proposed investigations would reveal novel insights into the mechanism by which PKC-delta regulates antiestrogen-resistance and the data should provide defined molecular target(s) for future clinical intervention for the treatment of breast cancer.