雌激素受体（ER）α的表达和相关信号传导是超过三分之二乳腺癌（BC）的主要驱动因素。ER靶向策略通常作为类固醇受体阳性（SR+）疾病患者的首选治疗方法。抗雌激素药物的次级抗药性可能会导致克隆扩张和疾病进展。激素耐药机制是一个具有重要转化意义的日益扩大的领域。其他核激素、受体和信号途径之间的交叉作用，包括甲状腺激素（TH）及其受体（THRs），在一些研究中已被证明能促进内分泌治疗耐药性。我们发现，在SR阳性（+）、无淋巴结转移（LN-）乳腺癌患者中，TH替代疗法（THRT）与复发和死亡率显著和独立地相关，而在SR阴性（-）患者中则没有相关性。接受THRT和他莫昔芬治疗的LN-、SR+患者有最糟糕的预后，这表明一种促癌相互作用，显著并独立地缩短生存时间和增加死亡率。我们先前在体内和体外模型中展示了激素的交叉作用、基因信号转导的改变、靶基因的激活以及在TH存在下对他莫昔芬的耐药性。在本研究中，我们展示了TH ± E2 ± 他莫昔芬会抑制细胞周期控制信号传导，减少细胞凋亡，增加细胞增殖、肿瘤生长、他莫昔芬的耐药性和克隆扩张。机制上，这些变化涉及众多基因和途径，包括利用各种分子方法鉴定的关键细胞周期调控蛋白和基因。这些研究有助于更好地理解TH对SR+乳腺癌的生物学和分子影响的机制。

Estrogen receptor (ER) α expression and associated signaling is a major driver of over two-thirds of all breast cancers (BC). ER targeting strategies are typically used as a first-line therapy in patients with steroid receptor positive (SR+) disease. Secondary resistance to anti-estrogenic agents may occur with clonal expansion and disease progression. Mechanisms underlying hormone resistance are an expanding field of significant translational importance. Cross-talk with other nuclear hormones, receptors, and signaling pathways, including thyroid hormones (TH) and their receptors (THRs), have been shown to promote endocrine therapy resistance in some studies. We have shown that TH replacement therapy (THRT) was independently and significantly associated with higher rates of relapse and mortality in SR positive (+), node-negative (LN-) BC patients, whereas it showed no association with outcomes in SR negative (-) patients. LN-, SR+ patients receiving THRT and tamoxifen had the worst outcomes, suggesting a pro-carcinogenic interaction that significantly and independently shortened survival and increased mortality. Using in vivo and in vitro models, we previously showed hormonal cross-talk, altered gene signaling, target gene activation, and resistance to tamoxifen in the presence of TH. In this report, we show TH ± E2 ± tamoxifen inhibits cell cycle control signaling, reduces apoptosis, and enhances cell proliferation, tumor growth, tamoxifen resistance, and clonal expansion. Mechanistically these changes involve numerous genes and pathways, including critical cell cycle regulatory proteins and genes identified using various molecular methods. These studies facilitate a greater mechanistic understanding of the biological and molecular impact of TH on SR+ BC.