Nat Med:雄激素受体:雌激素受体阳性乳腺癌的抑癌因子

2021-01-21 xiaozeng MedSci原创

在乳腺的发育过程中,雌激素(ER)能够刺激青春期后乳腺的生长,相反的,雄激素(AR)则会抑制该发育过程。

在乳腺的发育过程中,雌激素(ER)能够刺激青春期后乳腺的生长,相反的,雄激素(AR)则会抑制该发育过程。既往研究显示,ER是乳腺发育所必需的,其驱动了大多数的乳腺恶性肿瘤(约80%),然而AR的作用目前尚不明确。

在早期乳腺组织中激素受体尚不清楚的时候,雄激素曾用于治疗乳腺癌,其功效被认为是通过抑制下丘脑-垂体-性腺通路来实现的。由于毒副作用和直接靶向ER的药物的出现,最终终止了雄激素治疗策略。


目前,ER抑制剂是ER+乳腺癌的标准治疗方法,然而这些药物耐药性(内分泌耐药性)的产生是导致乳腺癌患者死亡的主要原因。因此,在患者的治疗替代策略中,雄激素治疗或可成为一个有力的手段。

雄激素在乳腺组织中抑制了雌激素诱导的细胞增殖作用

尽管如此,AR在ER+阳性乳腺癌中的作用目前仍有争议,这也限制了AR定向疗法的实施。


在该研究中,研究人员采用了多种临床相关的细胞系模型和患者衍生模型,证实了在多种疾病中AR的激活而非抑制作用发挥了有效的抗肿瘤活性,包括对标准治疗中的ER和CDK4/6抑制剂的抗性。值得注意的是,AR激动剂与标准治疗药物的联合使用可增强治疗反应。

AR活性在原发性ER+乳腺癌中的临床意义

机制研究显示,激动剂激活AR能够改变ER和必需的共激活因子(p300,SRC-3)的基因组分布,从而导致ER调控的细胞周期基因被抑制,包括已知的肿瘤抑制因子在内的AR靶基因的表达水平被上调。多个临床ER阳性的乳腺癌队列中AR活性这一基因标志能够预测疾病的生存状况。


总而言之,该研究结果提供了明确的证据,即在ER阳性乳腺癌中AR具有抑癌作用,而AR的激动剂或可作为最佳的AR导向性治疗策略


原始出处:

Hickey, T.E., Selth, L.A., Chia, K.M. et al. The androgen receptor is a tumor suppressor in estrogen receptor–positive breast cancer. Nat Med (18 January 2021).

 

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