Rajan Arathi, Varghese Geetu R, Yadev Induprabha, Anandan Jaimie, Latha Neetha R, Patra Dipyaman, Krishnan Neethu, Kuppusamy Krithiga, Warrier Arathy V, Bhushan Satej, Nadhan Revathy, Ram Kumar Ram Mohan, Srinivas Priya
Cancer Research Program, Rajiv Gandhi Centre for Biotechnology Thiruvananthapuram 695014, Kerala, India.
Department of Biotechnology, University of Kerala Thiruvananthapuram 695011, Kerala, India.
Am J Cancer Res. 2022 Jan 15;12(1):17-47. eCollection 2022.
BRCA1 mutation carriers have a greater risk of developing cancers in hormone-responsive tissues like breasts and ovaries. However, this tissue-specific incidence of BRCA1 related cancers remains elusive. The majority of the BRCA1 mutated breast cancers exhibit typical histopathological features of high-grade tumors, with basal epithelial phenotype, classified as triple-negative molecular subtype and have a higher percentage of DNA damage and chromosomal abnormality. Though there are many studies relating BRCA1 with ER-α (Estrogen receptor-α), it has not been reported whether E2 (Estrogen) -ER-α signaling can modulate the DNA repair activities of BRCA1. The present study analyzes whether deregulation of ER-α signaling, arising as a result of E2/ER-α deficiency, could impact the BRCA1 dependent DDR (DNA Damage Response) pathways, predominantly those of DNA-DSB (Double Strand break) repair and oxidative damage response. We demonstrate that E2/E2-stimulated ER-α can augment BRCA1 mediated high fidelity repairs like HRR (Homologous Recombination Repair) and BER (Base Excision Repair) in breast cancer cells. Conversely, a condition of ER-α deficiency itself or any interruption in ligand-dependent ER-α transactivation resulted in delayed DNA damage repair, leading to persistent activation of γH2AX and retention of unrepaired DNA lesions, thereby triggering tumor progression. ER-α deficiency not only limited the HRR in cells but also facilitated the DSB repair through error prone pathways like NHEJ (Non Homologous End Joining). ER-α deficiency associated persistence of DNA lesions and reduced expression of DDR proteins were validated in human mammary tumors.
携带BRCA1基因突变的个体患激素反应性组织（如乳腺和卵巢）癌症的风险更高。然而，BRCA1相关癌症的这种组织特异性发病率仍然难以捉摸。大多数BRCA1突变的乳腺癌表现出高级别肿瘤的典型组织病理学特征，具有基底上皮表型，归类为三阴性分子亚型，并且DNA损伤和染色体异常的比例更高。尽管有许多研究将BRCA1与雌激素受体α（ER-α）联系起来，但尚未报道雌激素（E2）-ER-α信号是否能调节BRCA1的DNA修复活性。本研究分析了由于E2/ER-α缺乏导致的ER-α信号失调是否会影响BRCA1依赖的DNA损伤反应（DDR）途径，主要是DNA双链断裂（DNA-DSB）修复和氧化损伤反应途径。我们证明，E2/雌激素刺激的ER-α可以增强乳腺癌细胞中BRCA1介导的高保真修复，如同源重组修复（HRR）和碱基切除修复（BER）。相反，ER-α缺乏本身或配体依赖性ER-α反式激活的任何中断都会导致DNA损伤修复延迟，导致γH2AX持续激活和未修复的DNA损伤保留，从而引发肿瘤进展。ER-α缺乏不仅限制了细胞中的HRR，还通过易错途径（如非同源末端连接（NHEJ））促进了DSB修复。在人类乳腺肿瘤中验证了与ER-α缺乏相关的DNA损伤持续存在和DDR蛋白表达降低。
