Department of Medicine, Division of Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
J Mol Endocrinol. 2020 Jul;65(1):T49-T63. doi: 10.1530/JME-20-0104.
Progesterone and progesterone receptors (PR) have a storied albeit controversial history in breast cancers. As endocrine therapies for breast cancer progressed through the twentieth 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 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 regulate diverse physiological processes in breast cancer cells. In the early 2000s, the somewhat surprising finding that prolonged use of synthetic progestin-containing menopausal hormone therapies was associated with increased 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 that are postulated to be the principal cells reactivated in occult or dormant disease. Other studies establish PR as dominant modulators of ER activity. Together, these findings mark PR as bona fide targets for progestin or antiprogestin 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 that PR regulate 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.
孕激素和孕激素受体（PR）在乳腺癌中有着丰富但颇具争议的历史。随着 20 世纪乳腺癌内分泌治疗从卵巢切除术到抗雌激素的发展，人们在 20 世纪 70 年代认识到，仅存在雌激素受体（ER）并不能有效地预测治疗反应。PR 是一种雌激素调节蛋白，成为预测内分泌治疗反应的第一个预后和预测标志物。它至今仍是预测乳腺癌恶性肿瘤中功能性、可靶向 ER 存在的金标准。随后发现 PR 是高度结构化的转录因子，可调节乳腺癌细胞中的多种生理过程。在 21 世纪初，令人有些惊讶的发现是，长期使用含有合成孕激素的绝经激素疗法与乳腺癌发病率增加有关，这引发了关于 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，这些干细胞被推测是隐匿性或休眠疾病中重新激活的主要细胞。其他研究确立了 PR 作为 ER 活性的主要调节剂。这些发现共同表明 PR 是孕激素或抗孕激素治疗的真正靶点，但它们的多种作用使这些治疗方法变得复杂。在这里，我们总结了 PR 在乳腺癌中的早期历史；驳斥了孕激素导致癌症的理论；讨论了最近的发现，即 PR 调节细胞异质性；试图统一描述 PR 作为肿瘤中好或坏的角色的理论；并讨论了可能有助于解释这种神秘激素和受体的新兴研究领域。
