甲状腺疾病与乳腺癌有关联。实际上，乳腺癌是甲状腺癌女性患者中最常见的继发恶性肿瘤（1）。此外，甲亢与女性乳腺癌风险增加11％（2）有关。重要的是，多达30％的乳腺癌患者因明显或亚临床甲状腺功能减退而接受甲状腺激素替代治疗（THRT）（3）。这些观察结果与临床前数据相结合，显示了甲状腺激素（THs）在各种癌症模型中的生长刺激效应（4），为 Wahdan-Alaswad等人的研究提供了依据目的在于研究THRT对非转移性乳腺癌患者结局的作用（3）。作者进行了一项观察性研究，分析了两个非转移性乳腺癌患者队列中THRT、无病存活（DFS）和特定疾病存活（DSS）之间的关联。第一队列包括820名患者，在1962年至1993年之间接受过乳腺癌治疗的患者，其中69名患者实施THRT，在中位随访期为10年。第二组纳入了更近期（2006年至2009年之间）接受治疗的160名患者，其中50名患者接受了THRT，并在中位随访期为8.8年。年龄、肿瘤大小、类固醇（雌/孕激素）受体（SR +/ SR-）的存在或不存在以及治疗方案的数据被纳入多元分析模型，分析DFS / DSS和5年及10年THRT之间的关联。为了更好地理解观察队列研究的结果，作者进行了功能体外和体内实验，以研究TH对乳腺癌细胞的分子机制，并测试雌激素受体（ER）和TH受体（THRs）之间的相互作用。在SR+乳腺癌患者中，THRT与复发的风险（DFS RR，2.9；P <0.001）和死亡（DSS RR，3.4；P <0.001）显着相关，与年龄、肿瘤大小和级别无关，而SR-乳腺癌患者的THRT不与更糟的结果有关。此外，接受芳香酶抑制剂联合THRT治疗的SR +乳腺癌患者的DFS更短（P <0.042），10年复发率更高（14％），而单独接受芳香酶抑制剂的患者为2％。功能体外和体内研究显示，单一治疗的TH或雌激素存在生长刺激作用，在ER +乳腺癌细胞系和小鼠异种移植瘤中进一步增强了联合治疗。RNA-Seq分析显示，联合治疗与细胞周期、错配修复、同源重组和DNA复制信号的显着激活以及诱导的甲状腺特异性基因和雌激素介导的特征有关。这些效应可以通过ER和/或THRa的沉默或抑制来消除，表明ERs和THRs的相互作用和核共定位是ER +乳腺癌模型中原癌性信号的主要驱动因素。该研究揭示了THRT与非转移性SR +乳腺癌患者的较差结果之间的临床重要联系，这很可能是由核ERs和THRs之间的相互作用推动的，并导致增加原癌性信号。这些结果表明，应避免在患有甲状腺功能减退症和同时患有乳腺癌患者中过度使用THRT。

Thyroid disorders have been associated with breast cancer. In fact, breast cancer is the most common secondary malignancy in female patients with thyroid cancer (1). Moreover, hyperthyroidism is associated with an 11% increased risk of breast cancer in women (2). Importantly, up to 30% of patients with breast cancer are treated with thyroid hormone replacement therapy (THRT) for overt or subclinical hypothyroidism (3). These observations, coupled with the preclinical data showing growth stimulatory effects of thyroid hormones (THs) in various cancer models (4), formed the rationale for the study by Wahdan-Alaswad et al. aimed at investigating the role of THRT on the outcome of patients with nonmetastatic breast cancer (3).The authors conducted an observational study analyzing the association between THRT, disease-free survival (DFS), and disease-specific survival (DSS) in two cohorts of patients with nonmetastatic breast cancer. The first cohort consistent of 820 patients followed for a median of 10 years and treated for breast cancer between 1962 and1993, with THRT implemented in 69 patients. The second cohort included 160 patients treated more recently (between 2006 and 2009) and followed for a median of 8.8 years, with 50 patients exposed to THRT. The data on the age, tumor size, presence or absence of steroid (estrogen and/or progesterone) receptors (SR+/SR-), and treatment regimen were incorporated in the multivariate model analyzing the association between DFS/DSS and THRT at 5 and 10 years. To better understand the results of the observational cohort study, the authors performed functional in vitro and in vivo experiments to investigate the molecular mechanisms underlying TH effects on breast cancer cells and to test the interactions between estrogen receptors (ERs) and TH receptors (THRs).In patients with SR+ breast cancer, THRT was associated with a significantly increased risk of recurrence (DFS RR, 2.9; P<0.001) and death (DSS RR, 3.4; P<0.001), independent of age, tumor size and grade, while THRT in patients with SR- breast cancer was not associated with worse outcomes. Moreover, patients with SR+ breast cancer undergoing therapy with aromatase inhibitor combined with THRT were characterized by a shorter DFS (P<0.042) and a higher 10-year recurrence rate of 14%, as compared with 2% in patient treated with the aromatase inhibitor alone.The functional in vitro and in vivo studies revealed growth stimulatory effects of monotherapy with TH or estrogens that were further potentiated with combination therapy in ER+ breast cancer cell lines and mice xenografts. The RNA-Seq analysis revealed that combination therapy was associated with a significant activation of the cell cycle, mismatch repair, homologous recombination, and DNA replication signaling, as well as induced thyroid-specific genes and estrogen-mediated signatures. These effects were abrogated by the knockdown or inhibition of ER and/or THRa, suggesting that cross-talk and nuclear colocalization of ERs and THRs are major drivers of pro-oncogenic signaling in the ER+ breast cancer model.The study reveals clinically significant associations between THRT and worse outcomes in patients with nonmetastatic SR+ breast cancer that are likely driven by interactions between the nuclear ERs and THRs, leading to upregulation of pro-oncogenic signaling. These results suggest that overuse of THRT in patients with hypothyroidism and concurrent breast cancer should be avoided.