PDF(Pubmed)
Abstract：
Endocrine resistance poses a significant clinical challenge for patients with hormone receptor-positive and human epithelial growth factor receptor 2-negative (HR + HER2-) breast cancer. Dysregulation of estrogen receptor (ER) and ERBB signaling pathways is implicated in resistance development; however, the integration of these pathways remains unclear. While SMAD4 is known to play diverse roles in tumorigenesis, its involvement in endocrine resistance is poorly understood. Here, we investigate the role of SMAD4 in acquired endocrine resistance in HR + HER2- breast cancer. Genome-wide CRISPR screening identifies SMAD4 as a regulator of 4-hydroxytamoxifen (OHT) sensitivity in T47D cells. Clinical data analysis reveals downregulated SMAD4 expression in breast cancer tissues, correlating with poor prognosis. Following endocrine therapy, SMAD4 expression is further suppressed. Functional studies demonstrate that SMAD4 depletion induces endocrine resistance in vitro and in vivo by enhancing ER and ERBB signaling. Concomitant inhibition of ER and ERBB signaling leads to aberrant autophagy activation. Simultaneous inhibition of ER, ERBB, and autophagy pathways synergistically impacts SMAD4-depleted cells. Our findings unveil a mechanism whereby endocrine therapy-induced SMAD4 downregulation drives acquired resistance by integrating ER and ERBB signaling and suggest a rational treatment strategy for endocrine-resistant HR + HER2- breast cancer patients.
摘要：
内分泌耐药对激素受体阳性和人上皮生长因子受体2阴性（HR+HER2-）乳腺癌患者构成重大临床挑战。雌激素受体（ER）和ERBB信号通路的失调与抗性发展有关；然而，这些途径的整合仍不清楚.虽然已知SMAD4在肿瘤发生中起着不同的作用，它与内分泌抵抗的关系知之甚少。这里,我们研究了SMAD4在HR+HER2-乳腺癌获得性内分泌耐药中的作用.全基因组CRISPR筛选将SMAD4鉴定为T47D细胞中4-羟基他莫昔芬(OHT)敏感性的调节剂。临床数据分析显示乳腺癌组织中SMAD4表达下调，与预后不良有关。内分泌治疗后,SMAD4的表达被进一步抑制。功能研究表明，SMAD4消耗通过增强ER和ERBB信号传导在体外和体内诱导内分泌抗性。ER和ERBB信号的伴随抑制导致异常的自噬激活。同时抑制ER，ERBB,和自噬途径协同影响SMAD4耗竭细胞。我们的发现揭示了内分泌治疗诱导的SMAD4下调通过整合ER和ERBB信号驱动获得性耐药的机制，并为内分泌耐药HR+HER2-乳腺癌患者提出了合理的治疗策略。
