Crosstalk between BRCA1 and Transcription in Breast Cancer

摘要 大多数BRCA1相关的乳腺肿瘤是基底样瘤，但它们起源于腔前体细胞。 BRCA1在双链断裂(DSB)修复和DNA复制应激反应中发挥重要作用。 然而，BRCA1的这些无处不在的重要功能是否足够，仍然是一个谜 以解释其细胞谱系特异性的乳腺肿瘤抑制作用。填补这一长期的智力鸿沟 可以为更有效的风险评估和疾病预防提供信息。我们的小鼠遗传学研究发现 BRCA1和专用转录延伸因子COBRA1之间的意外功能拮抗 对腔基因转录很重要。这种BRCA1/COBRA1串扰调节管腔祖细胞功能， 腔转录相关的DSB前体与DSB修复非依赖的乳腺肿瘤发生 举止。在一项使用临床样本的平行研究中，我们发现无癌症的BRCA1突变携带者 在他们的乳腺腔上皮细胞中特异地积累DSB前体。在此基础上，我们 假设，通过它与依赖于COBRA1的转录延伸机制的串扰， BRCA1阻止DSB前体在腔基因的优先积累，从而减少 腔细胞间基因组的不稳定性。我们将利用小鼠遗传学和临床样本 阐明BRCA1/COBRA1拮抗对腔内稳态、DSB前体产生和 乳房肿瘤的发生。在我们提议的工作中要验证的概念显然与流行的 以DNA修复为中心的范式。此外，不依赖DNA修复的BRCA1/COBRA1拮抗点 在阐明BRCA1抑癌基因功能和预防肿瘤方面取得了前所未有的进展 BRCA1相关乳腺癌。当成功执行时，我们的研究承诺奠定坚实的概念性 基金会调和关于BRCA1相关乳腺癌的持久脱节，从而引发 对BRCA1癌症生物学的认识上了一个新的台阶。

ABSTRACT Most BRCA1-asociated breast tumors are basal-like, yet they originate from luminal progenitor cells. BRCA1 plays important roles in double strand break (DSB) repair and response to DNA replication stress. However, it remains a conundrum as to whether these ubiquitously important functions of BRCA1 are sufficient to account for its cell lineage-specific breast tumor suppression. Filling this longstanding intellectual disconnect could inform more effective risk assessment and disease prevention. Our mouse genetics work identified unexpected functional antagonism between BRCA1 and COBRA1, a dedicated transcription elongation factor important for luminal gene transcription. This BRCA1/COBRA1 crosstalk regulates luminal progenitor function, luminal transcription-related DSB precursors, and mammary tumorigenesis in a DSB repair-independent manner. In a parallel investigation using clinical samples, we found that cancer-free BRCA1 mutation carriers accumulate DSB precursors specifically in their breast luminal epithelial cells. Based on this groundwork, we hypothesize that, through its crosstalk with COBRA1-dependent transcription elongation machinery, BRCA1 prevents preferential accumulation of DSB precursors at luminal genes and thus reduces genome instability in luminal cell compartment. We will use mouse genetics and clinical samples to elucidate the impact of BRCA1/COBRA1 antagonism on luminal homeostasis, DSB precursor production, and breast tumorigenesis. The concept to be validated in our proposed work clearly departs from the prevailing DNA repair-centric paradigm. Furthermore, the DNA repair-independent BRCA1/COBRA1 antagonism points to a previously unappreciated direction for elucidating BRCA1 tumor suppressor function and preventing BRCA1-associated breast cancer. When successfully executed, our studies promises to lay a solid conceptual foundation to reconcile an enduring disconnect concerning BRCA1-associated breast cancer, thus catapulting understanding of BRCA1 cancer biology to a new level.