The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer.
The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer.
复制标题
DOI：
10.1530/erc-14-0448
复制
发表时间：
2015-02
影响因子：
3.9
通讯作者：
Jordan VC
中科院分区：
文献类型：
--
作者：
Jordan VC
成功使用高剂量合成雌激素治疗绝经后转移性乳腺癌，是第一个在临床试验中证明有效的“化学疗法”治疗任何癌症。本综述记录了雌激素用于乳腺癌治疗或雌激素替代疗法（ERT）用于绝经后乳腺癌切除术后妇女的临床应用，这些治疗可导致乳腺癌细胞生长或乳腺癌消退。自20世纪50年代以来，这一直是一个悖论，直到世纪末发现雌激素诱导细胞凋亡的新生物学。用雌激素触发细胞凋亡的关键是选择对长期雌激素剥夺有抗性的乳腺癌细胞群。然而，通过试验和错误，雌激素独立生长发生。在细胞水平，雌激素诱导的细胞凋亡依赖于雌激素受体（ER）的存在，其可以被非甾体或甾体抗雌激素阻断。雌激素配体的形状程序的ER复合物的构象，这反过来又可以调节雌激素诱导的细胞凋亡：I类平面雌激素（例如：雌二醇）触发细胞凋亡后24小时，而II类角雌激素（例如：双酚三苯乙烯）延迟的过程，直到72小时后。这与紫杉醇形成对比，紫杉醇导致G2阻滞并立即发生细胞凋亡。该过程在24小时内完成。雌激素诱导的细胞凋亡受糖皮质激素和cSrc抑制剂的调节，但雌激素作用的靶机制是基因组的，而不是通过非基因组途径。该过程是逐步通过创建内质网应激和炎症反应，然后启动未折叠的蛋白质反应。这又通过内在途径（线粒体）启动凋亡，随后募集外在途径（死亡受体）以完成该过程。临床和实验室研究的对称性现在允许为ERT或植物雌激素补充剂的未来临床应用创建规则：绝经后需要五年的间隔，以允许选择雌激素缺乏的乳腺癌细胞群，使其易受凋亡细胞死亡的影响。在绝经期早期用雌激素治疗会促进ER阳性肿瘤细胞的生长，因为这些细胞仍然依赖雌激素来维持在不断扩大的群体中的复制。对与雌激素诱导的细胞凋亡相关的分子事件可以在实验室中在雌激素剥夺的乳腺癌中被精心安排的证据的认识，现在支持了在雌激素剥夺后治疗转移性乳腺癌的临床发现，长期抗激素辅助治疗后死亡率降低，以及女性健康倡议中针对60岁以上女性的ERT和ERT加阿托伐他汀的结果。原则已经出现，以了解和应用生理雌激素治疗适当针对正确的患者人群。
The successful use of high dose synthetic estrogens to treat post-menopausal metastatic breast cancer, is the first effective “chemical therapy” proven in clinical trial to treat any cancer. This review documents the clinical use of estrogen for breast cancer treatment or estrogen replacement therapy (ERT) for postmenopausal hysterectomized women which can either result in breast cancer cell growth or breast cancer regression. This has remained a paradox since the 1950s until the discovery of the new biology of estrogen induced apoptosis at the end of the 20th century. The key to triggering apoptosis with estrogen is the selection of breast cancer cell populations that are resistant to long term estrogen deprivation. However, through trial and error estrogen independent growth occurs. At the cellular level, estrogen induced apoptosis is dependent upon the presence of the estrogen receptor (ER) which can be blocked by non-steroidal or steroidal anti-estrogens. The shape of an estrogenic ligand programs the conformation of the ER complex which in turn can modulate estrogen induced apoptosis: class I planar estrogens (eg: estradiol) trigger apoptosis after 24 hours whereas class II angular estrogens (eg: bisphenol triphenylethylene) delay the process until after 72 hours. This contrasts with paclitaxel that causes G2 blockade with immediate apoptosis. The process is complete within 24 hours. Estrogen induced apoptosis is modulated by glucocorticoids and cSrc inhibitors but the target mechanism for estrogen action is genomic and not through a non-genomic pathway. The process is step wise through the creation of endoplasmic reticulum stress and, inflammatory responses that then initiate an unfolded protein response. This in turn initiates apoptosis through the intrinsic pathway (mitochondrial) with subsequent recruitment of the extrinsic pathway (death receptor) to complete the process. The symmetry of the clinical and laboratory studies now permits the creation of rules for the future clinical application of ERT or phytoestrogen supplements: a five year gap is necessary after menopause to permit the selection of estrogen deprived breast cancer cell populations to become vulnerable to apoptotic cell death. Earlier treatment with estrogen around the menopause encourages ER positive tumor cell growth, as the cells are still dependent on estrogen to maintain replication within the expanding population. An awareness of the evidence that the molecular events associated with estrogen induced apoptosis can be orchestrated in the laboratory in estrogen deprived breast cancers, now support the clinical findings for the treatment of metastatic breast cancer following estrogen deprivation, decreases in mortality following long term antihormonal adjuvant therapy, and the results of ERT and ERT plus progestin in the Women’s Health Initiative for women over the age of 60. Principles have emerged to understand and apply physiologic estrogen therapy appropriately by targeting the correct patient populations.