90 YEARS OF PROGESTERONE: Progesterone and progesterone receptors in breast cancer: past, present, future.
90 YEARS OF PROGESTERONE: Progesterone and progesterone receptors in breast cancer: past, present, future.
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DOI：
10.1530/jme-20-0104
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发表时间：
2020-07
影响因子：
3.5
通讯作者：
Sartorius CA
中科院分区：
文献类型：
--
作者：
Horwitz KB;Sartorius CA
孕激素和孕激素受体（PR）在乳腺癌中有着传奇的历史，尽管存在争议。随着乳腺癌的内分泌治疗在整个世纪从卵巢切除术发展到抗雌激素治疗，在20世纪70年代认识到仅雌激素受体（ER）的存在不能有效地预测治疗反应。PR是一种雌激素调节蛋白，成为内分泌治疗反应的第一个预后和预测标志物。它仍然在临床上使用今天作为金标准预测功能性，靶向ER的存在，在乳腺恶性肿瘤。PR随后被鉴定为决定乳腺癌细胞中各种生理过程的高度结构化的转录因子。在21世纪初，有些令人惊讶的发现，即长期使用含孕激素的合成绝经激素疗法会增加乳腺癌的发病率，这提出了关于PR在“肿瘤发生”中的作用的新问题。最近，PR与癌症干细胞的扩增有关，并被认为是在隐匿性或休眠性疾病中重新激活的主要细胞。其他研究确立PR为ER活性的主要调节剂。综合这些发现，PR是基于孕激素或抗孕激素治疗的真正目标，但它们的不同作用混淆了这种用途。在这里，我们总结了乳腺癌PR的早期历史;揭穿了孕酮导致癌症的理论;讨论了最近的发现，涉及PR在调节细胞异质性;试图统一理论描述PR在肿瘤中的好或坏的演员;并讨论了新兴的研究领域，可能有助于解释这种神秘的激素和受体。
Progesterone and progesterone receptors (PR) have a storied albeit controversial history in breast cancers. As endocrine therapies for breast cancer progressed through the 20th century from oophorectomy to antiestrogens, it was recognized in the 1970s that the presence of estrogen receptors (ER) alone could not efficiently predict treatment responses. PR, an estrogen regulated protein, became the first prognostic and predictive marker of response to endocrine therapies. It remains in clinical use today as the gold standard for predicting the existence of functional, targetable ER, in breast malignancies. PRs were subsequently identified as highly structured transcription factors that dictate a variety of physiological processes in breast cancer cells. In the early 2000s, the somewhat surprising finding that prolonged use of synthetic progestin-containing menopausal hormone therapies increase breast cancer incidence raised new questions about the role of PR in “tumorigenesis”. Most recently, PR have been linked to expansion of cancer stem cells, and postulated to be the principal cells reactivated in occult or dormant disease. Other studies establish PR as dominant modulators of ER activity. Taken together these findings mark PR as bona fide targets for progestin- or antiprogestin-based therapies, yet their diverse actions have confounded that use. Here we summarize the early history of PR in breast cancer; debunk the theory that progesterone causes cancer; discuss recent discoveries implicating PR in regulation of cell heterogeneity; attempt to unify theories describing PR as either good or bad actors in tumors; and discuss emerging areas of research that may help explain this enigmatic hormone and receptor.