Sutherland Lincoln, Lang Jacob, Gonzalez-Juarbe Norberto, Pickett Brett E
Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT 84602, USA.
J. Craig Venter Institute, Rockville, MD 20850, USA.
Curr Issues Mol Biol. 2024 Jul 6;46(7):7114-7133. doi: 10.3390/cimb46070424.
Estrogen receptor-positive (ER+) breast cancer is common among postmenopausal women and is frequently treated with Letrozole, which inhibits aromatase from synthesizing estrogen from androgens. Decreased estrogen slows the growth of tumors and can be an effective treatment. The increase in Letrozole resistance poses a unique problem for patients. To better understand the underlying molecular mechanism(s) of Letrozole resistance, we reanalyzed transcriptomic data by comparing individuals who responded to Letrozole therapy (responders) to those who were resistant to treatment (non-responders). We identified and as two significant differentially expressed genes (DEGs) between these patient cohorts, with "PLK1 signaling events" being the most significant signaling pathway. We also identified and gene products as being the top mechanistic transcriptional markers for ER+ treatment resistance. Many of the significant DEGs that we identified play a known role in ER+ breast cancer or other types of cancer, which partially validate our results. Several of the gene products we identified are novel in the context of ER+ breast cancer. Many of the genes that we identified warrant further research to elucidate the more specific molecular mechanisms of Letrozole resistance in this patient population and could potentially be used as prognostic markers with further wet lab validation. We anticipate that these findings could contribute to improved detection and therapeutic outcomes in aromatase-resistant ER+ breast cancer patients.
雌激素受体阳性（ER+）乳腺癌在绝经后女性中很常见，通常用来曲唑治疗，来曲唑可抑制芳香化酶将雄激素合成雌激素。雌激素水平降低会减缓肿瘤生长，是一种有效的治疗方法。来曲唑耐药性的增加给患者带来了一个独特的问题。为了更好地理解来曲唑耐药的潜在分子机制，我们通过比较来曲唑治疗有反应的个体（反应者）和对治疗耐药的个体（无反应者），重新分析了转录组数据。我们确定了[具体基因1]和[具体基因2]是这两组患者队列之间两个显著差异表达的基因（DEGs），“PLK1信号事件”是最显著的信号通路。我们还确定了[具体基因3]和[具体基因4]的基因产物是ER+治疗耐药的主要机制转录标志物。我们确定的许多显著DEGs在ER+乳腺癌或其他类型的癌症中发挥着已知作用，这部分验证了我们的结果。我们确定的几种基因产物在ER+乳腺癌的背景下是新发现的。我们确定的许多基因值得进一步研究，以阐明该患者群体中来曲唑耐药的更具体分子机制，并有可能在进一步的湿实验室验证后用作预后标志物。我们预计这些发现可能有助于改善芳香化酶耐药的ER+乳腺癌患者的检测和治疗结果。
