Resistance to Antiestrogen Therapy in Hormone Receptor-Positive Breast Cancer

激素受体阳性乳腺癌的治疗包括旨在阻断雌激素作用的疗法。尽管这些治疗改变了乳腺癌的自然病程，但许多肿瘤表现出新生或获得性内分泌抵抗。对人乳腺癌细胞系的研究以及原发性乳腺肿瘤的分子谱分析已经确定了与乳腺癌相关的分子改变。 激素不依赖性和抗药性这些机制之一是HER 2（ErbB 2）原癌基因及其信号网络的过度表达。HER 2过表达是抗雌激素抵抗的唯一机制，存在前瞻性临床数据。然而，只有<10%的依赖性 乳腺癌表达高水平的HER 2，这表明对于大多数HER 2受体阳性乳腺癌，逃避内分泌治疗的机制仍有待发现。除了抗雌激素治疗的实质性改善外，还开发了预测其获益几率的检测方法，但这些检测方法不能识别与治疗失败和肿瘤复发相关的分子改变。最近，新辅助激素治疗后肿瘤标本中通过Ki 67免疫组织化学测定的癌细胞增殖已显示与无病生存期和总生存期相关。这些数据表明，乳腺肿瘤内分泌治疗的细胞和分子效应的药效学生物标志物，可能是因为它们结合了治疗的效果，可用于识别高度依赖性的癌症，因此对内分泌治疗敏感，而不是那些新生耐药和/或注定复发更快的癌症。我们推测，那些表现出明显抑制细胞增殖的肿瘤可能在单独的辅助激素治疗中表现良好，而那些没有表现出明显抑制细胞增殖的肿瘤则注定会早期复发。为了1）确定抑制HER 2功能是否逆转对内分泌治疗的抵抗，和2）发现与无HER 2过表达的激素受体阳性肿瘤对内分泌治疗的抵抗相关的新机制，我们 提出以下目标： 目的1：确定芳香化酶抑制剂来曲唑和HER 2联合新辅助治疗 酪氨酸激酶抑制剂拉帕替尼诱导激素受体阳性的病理完全反应 过表达HER 2的乳腺癌，并建立预测对该疗法的反应的生物标志物。 目标二：确定激素受体阳性/HER 2阴性肿瘤中来曲唑给药后Ki 67是否反映了通过福尔马林固定的肿瘤组织切片中21个选定基因的RT-PCR测量的复发评分，并使用这些生物标志物发现与激素依赖相关的基因表达特征。 目标3：确定激素受体阳性乳腺癌细胞中PTEN缺失导致磷脂酰肌醇-3激酶（PI 3 K）信号转导失调并产生抗雌激素抗性的机制。

The treatment for hormone receptor-positive breast cancer includes therapies designed to block estrogen action. Although these therapies have changed the natural history of hormone-dependent breast cancer, many tumors exhibit ofe novo or acquired endocrine resistance. Studies with human breast cancer cell lines as well as molecular profiling of primary mammary tumors have identified molecular alterations associated with hormonal independence and drug resistance. One of these mechanisms is overexpression of the HER2 (ErbB2) protooncogene and its signaling network. Overexpression of HER2 is the only mechanism of antiestrogen resistance for which prospective clinical data exist. However, only <10% of hormone-dependent breast cancer express high levels of HER2, suggesting that for the majority of hormone-receptor positive breast cancers, mechanisms of escape from endocrine therapy remain to be discovered. In addition to the substantial improvements of antiestrogen therapy, assays have been developed to predict the odds of benefit from it. These assays do not identify the molecular alteration causally associated with treatment failure and tumor recurrence. More recently, cancer cell proliferation as measured by Ki67 immunohistochemistry in the tumor specimen after neoadjuvant hormonal therapy has been shown to correlate with disease-free and overall survival. These data suggest that pharmacodynamic biomarkers of the cellular and molecular effects of endocrine therapy in the breast tumor, likely because they incorporate the effects of therapy, can be used to identify cancers that are highly hormone-dependent and thus sensitive to endocrine treatment vs. those that are cfe novo resistant and/or destined to recur faster. We hypothesize that those tumors exhibiting a marked inhibition of cell proliferation are likely to do well on adjuvant hormonal therapy alone whereas those that do not, are destined to an early recurrence. To 1) determine if inhibition of HER2 function reverses resistance to endocrine therapy, and 2) discover novel mechanisms associated with resistance to endocrine therapy in hormone receptor-positive tumors without HER2 overexpression, we propose the following aims: Aim 1: To determine if combined neoadjuvant therapy with the aromatase inhibitor letrozole and the HER2 tyrosine kinase inhibitor lapatinib induces pathologic complete responses in hormone receptor-positive breast cancers that overexpress HER2 and establish biomarkers predictive of response to this therapy. Aim 2: To determine if the post-letrozole Ki67 in hormone receptor-positive/HER2-negative tumors mirrors the recurrence score as measured by RT-PCR of 21 selected genes in formalin-fixed tumor tissue sections and to use these biomarkers to discover gene expression signatures associated with hormonal dependence. Aim 3: To determine the mechanisms by which loss of PTEN in hormone receptor-positive breast cancer cells dysregulates phosphatidylinositol-3 kinase (PI3K) signaling and generates resistance to antiestrogens.