Department of Medical Oncology, The First Affiliated hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China.
Molecular Oncology Program, Division of Surgical Oncology, Dewitt Daughtry Family Department of Surgery, University of Miami, Miami, FL, 33136, USA.
Breast Cancer Res. 2018 Jul 11;20(1):74. doi: 10.1186/s13058-018-0996-9.
Estrogen promotes breast cancer development and progression mainly through estrogen receptor (ER). However, blockage of estrogen production or action prevents development of and suppresses progression of ER-negative breast cancers. How estrogen promotes ER-negative breast cancer development and progression is poorly understood. We previously discovered that deletion of cell cycle inhibitors p16 (p16) or p18 (p18) is required for development of Brca1-deficient basal-like mammary tumors, and that mice lacking p18 develop luminal-type mammary tumors.
A genetic model system with three mouse strains, one that develops ER-positive mammary tumors (p18 single deletion) and the others that develop ER-negative tumors (p16;Brca1 and p18;Brca1 compound deletion), human BRCA1 mutant breast cancer patient-derived xenografts, and human BRCA1-deficient and BRCA1-proficient breast cancer cells were used to determine the role of estrogen in activating epithelial-mesenchymal transition (EMT), stimulating cell proliferation, and promoting ER-negative mammary tumor initiation and metastasis.
Estrogen stimulated the proliferation and tumor-initiating potential of both ER-positive Brca1-proficient and ER-negative Brca1-deficient tumor cells. Estrogen activated EMT in a subset of Brca1-deficient mammary tumor cells that maintained epithelial features, and enhanced the number of cancer stem cells, promoting tumor progression and metastasis. Estrogen activated EMT independent of ER in Brca1-deficient, but not Brca1-proficient, tumor cells. Estrogen activated the AKT pathway in BRCA1-deficient tumor cells independent of ER, and pharmaceutical inhibition of AKT activity suppressed EMT and cell proliferation preventing BRCA1 deficient tumor progression.
This study reveals for the first time that estrogen promotes BRCA1-deficient tumor initiation and progression by stimulation of cell proliferation and activation of EMT, which are dependent on AKT activation and independent of ER.
雌激素主要通过雌激素受体（ER）促进乳腺癌的发生和发展。然而，阻止雌激素的产生或作用会阻止 ER 阴性乳腺癌的发展并抑制其进展。雌激素如何促进 ER 阴性乳腺癌的发生和发展尚不清楚。我们之前发现，Brca1 缺陷的基底样乳腺肿瘤的发展需要细胞周期抑制剂 p16（p16）或 p18（p18）的缺失，并且缺乏 p18 的小鼠会发展出腔型乳腺肿瘤。
使用三种小鼠品系的遗传模型系统，一种品系发展出 ER 阳性乳腺肿瘤（p18 单一缺失），另两种品系发展出 ER 阴性肿瘤（p16；Brca1 和 p18；Brca1 复合缺失），人 BRCA1 突变型乳腺癌患者来源的异种移植物，以及人 BRCA1 缺陷型和 BRCA1 功能正常型乳腺癌细胞，来确定雌激素在激活上皮-间充质转化（EMT）、刺激细胞增殖以及促进 ER 阴性乳腺肿瘤起始和转移中的作用。
雌激素刺激了 ER 阳性 Brca1 功能正常型和 ER 阴性 Brca1 缺陷型肿瘤细胞的增殖和肿瘤起始能力。雌激素激活了一小部分 Brca1 缺陷型乳腺肿瘤细胞中的 EMT，这些细胞保留了上皮特征，并增加了癌症干细胞的数量，促进了肿瘤的进展和转移。雌激素在 Brca1 缺陷型肿瘤细胞中激活 EMT 不依赖于 ER，但在 Brca1 功能正常型肿瘤细胞中则不依赖于 ER。雌激素在 BRCA1 缺陷型肿瘤细胞中激活 AKT 通路不依赖于 ER，而 AKT 活性的药物抑制抑制了 EMT 和细胞增殖，从而阻止了 BRCA1 缺陷型肿瘤的进展。
这项研究首次揭示了雌激素通过刺激细胞增殖和激活 EMT 来促进 BRCA1 缺陷型肿瘤的起始和进展，这依赖于 AKT 的激活，而不依赖于 ER。
