Microarray expression profiling data for Trp53/Brca1-null mammary tumors derived from K8+ luminal cells

BRCA1 mutation-carriers are predisposed to develop Basal-like breast cancer (BLBC), and p53 mutations are present in the majority of human BLBC cases, suggesting loss of these two tumor suppressors play key roles in development of BLBC. Recent studies suggest that the majority of human breast cancers, including BLBC, may originate from mammary epithelial cells (MECs) in the luminal lineage. However, how loss of p53 and BRCA1 contributes to development of BLBC from luminal MECs remains largely elusive. We developed a novel genetic targeting and lineage tracing approach based on intraductal injection of Cre-expressing adenovirus under the control of the pan-luminal Keratin 8 (K8) promoter (Ad-K8-Cre). We performed intraductal injection of Ad-K8-Cre to female mice carrying conditional knockout alleles of Brca1 and Trp53. The injected females developed mammary tumors within 12 months after injection. Microarray expression profiling of these tumors showed that they most closely resembled human BLBC. Total RNAs from YFP+ wild-type luminal mammary epithelial cells (i.e., cells of origin) sorted from Rosa26-Stop-YFP female mice 10-14 days after intraductal induction of Ad-K8-Cre adenovirus, or from mammary tumors developed in Trp53L/L;Brca1L/L females several months after intraductal injection of Ad-K8-Cre, were prepared and subjected to microarray expression profiling.

BRCA1突变携带者易患基底样乳腺癌（Basal-like breast cancer, BLBC），且p53突变存在于大多数人类BLBC病例中，提示这两种抑癌基因的缺失在BLBC的发生发展中发挥关键作用。近期研究表明，包括BLBC在内的绝大多数人类乳腺癌可能起源于管腔谱系的乳腺上皮细胞（mammary epithelial cells, MECs）。然而，p53与BRCA1的缺失如何从管腔MECs驱动BLBC的发生，目前在很大程度上仍不明确。本研究开发了一种基于泛管腔角蛋白8（Keratin 8, K8）启动子调控的Cre表达腺病毒（Ad-K8-Cre）导管内注射的新型基因靶向与谱系示踪方法。我们对携带Brca1与Trp53条件性敲除等位基因的雌性小鼠实施了Ad-K8-Cre导管内注射，接受注射的雌性小鼠在注射后12个月内即可长出乳腺肿瘤。对这些肿瘤的微阵列表达谱分析显示，其分子特征与人类BLBC最为相似。我们分别制备了两类样本的总RNA并进行微阵列表达谱分析：一类是在Ad-K8-Cre腺病毒导管内诱导10~14天后，从Rosa26-Stop-YFP雌性小鼠中分选得到的YFP阳性野生型管腔乳腺上皮细胞（即细胞起源）；另一类是在Ad-K8-Cre导管内注射数月后，从Trp53L/L;Brca1L/L雌性小鼠体内形成的乳腺肿瘤组织。