Hasson Shira Peleg, Rubinek Tami, Ryvo Larysa, Wolf Ido
Institute of Oncology, Tel Aviv Sourasky Medical Center, Israel ; Sackler Faculty of Medicine, Tel Aviv University, Israel.
Institute of Oncology, Tel Aviv Sourasky Medical Center, Israel.
Breast Care (Basel). 2013 Aug;8(4):248-55. doi: 10.1159/000354757.
Breast cancer is the most common cancer among women. Up to 75% of breast cancers express the estrogen receptor (ER)α and/or the progesterone receptor (PR). Patients with hormone receptor-positive metastatic breast cancer are typically treated with endocrine therapy. Yet, not all patients with metastatic breast cancer respond to endocrine treatments and are considered to have primary (de novo) resistance. Furthermore, all patients who initially respond to endocrine treatment will eventually develop acquired resistance. Several mechanisms have been linked to the development of endocrine resistance, including reduced expression of ERα, altered regulation of the ER pathway, and activation of various growth factor signaling pathways, among them the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway. This pathway is involved in critical processes including cell survival, proliferation, and angiogenesis, and plays a central role in breast cancer development. Recent laboratory and clinical data implicate this pathway as mediating endocrine resistance, and agents directed against critical components of this pathway are either already approved for clinical use in breast cancer patients or are currently being tested in clinical trials. In this review, we describe the interaction between the PI3K/Akt/mTOR pathway and the ER cascade, its role in mediating endocrine resistance, and the clinical implications of this interaction.
乳腺癌是女性中最常见的癌症。高达75%的乳腺癌表达雌激素受体（ER）α和/或孕激素受体（PR）。激素受体阳性转移性乳腺癌患者通常接受内分泌治疗。然而，并非所有转移性乳腺癌患者都对内分泌治疗有反应，这些患者被认为具有原发性（新发）耐药性。此外，所有最初对内分泌治疗有反应的患者最终都会产生获得性耐药。几种机制与内分泌耐药的发生有关，包括ERα表达降低、ER信号通路调控改变以及各种生长因子信号通路的激活，其中包括磷脂酰肌醇3激酶（PI3K）/蛋白激酶B（Akt）/雷帕霉素哺乳动物靶蛋白（mTOR）信号通路。该信号通路参与包括细胞存活、增殖和血管生成在内的关键过程，在乳腺癌发展中起核心作用。最近的实验室和临床数据表明该信号通路介导内分泌耐药，针对该信号通路关键成分的药物要么已被批准用于乳腺癌患者的临床治疗，要么正在临床试验中进行测试。在本综述中，我们描述了PI3K/Akt/mTOR信号通路与ER级联反应之间的相互作用、其在介导内分泌耐药中的作用以及这种相互作用的临床意义。
