Crosstalk between BRCA1 and Transcription in Breast Cancer

摘要 大多数BRCA 1相关的乳腺肿瘤是基底样的，但它们起源于管腔祖细胞。 BRCA 1在双链断裂修复和DNA复制应激反应中起重要作用。 然而，BRCA 1的这些普遍重要的功能是否足够仍然是一个难题 以解释其细胞系特异性乳腺肿瘤抑制。填补了这一长期存在的智力脱节 可以为更有效的风险评估和疾病预防提供信息。我们的老鼠遗传学研究发现 BRCA 1和COBRA 1之间的意外功能拮抗作用，COBRA 1是一种专用的转录延伸因子 对管腔基因转录很重要。这种BRCA 1/COBRA 1串扰调节管腔祖细胞功能， 管腔转录相关的DSB前体和DSB修复独立的乳腺肿瘤发生 方式在一项使用临床样本的平行调查中，我们发现无癌BRCA 1突变携带者 在其乳腺腔上皮细胞中特异性地积累DSB前体。在此基础上，我们 假设，通过与COBRA 1依赖性转录延伸机制的串扰， BRCA 1阻止DSB前体在管腔基因处的优先积累，从而减少了DSB前体在管腔基因处的表达。 腔细胞区室中的基因组不稳定性。我们将使用小鼠遗传学和临床样本， 阐明BRCA 1/COBRA 1拮抗作用对管腔内稳态、DSB前体产生和 乳腺肿瘤发生在我们拟议的工作中要验证的概念显然不同于目前流行的概念。 DNA修复中心范式。此外，DNA修复非依赖性BRCA 1/COBRA 1拮抗作用点 以前未被重视的方向，阐明BRCA 1肿瘤抑制功能和预防 BRCA 1相关乳腺癌。当成功执行时，我们的研究有望奠定坚实的概念 基金会调和关于BRCA 1相关乳腺癌的持久脱节，从而使乳腺癌的发病率下降。 将BRCA 1癌症生物学的理解提高到一个新的水平。

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.