Cell lineage tracing links ERα loss in Erbb2-positive breast cancers to the arising of a highly aggressive breast cancer subtype
Cell lineage tracing links ERα loss in Erbb2-positive breast cancers to the arising of a highly aggressive breast cancer subtype
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DOI：
10.1073/pnas.2100673118
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发表时间：
2021-05-25
影响因子：
11.1
通讯作者：
Xu, Jianming
中科院分区：
文献类型：
--
作者：
Ding, Yunfeng;Liu, Yonghong;Xu, Jianming
HER 2阳性（HER 2 *）乳腺癌（BrC）含有大约相等数量的ER α * HER 2 * 和ER α-HER 2 * 病例。一个持久的障碍是这些BrCs的细胞系相关特征不清楚。虽然ER α * HER 2 * BrC可能失去ER α而成为ER α-HER 2 * BrC，但缺少直接证据。为了研究ER α依赖性及其在BrC生长和转移过程中的意义，我们产生了产生RFP标记的ER α * 乳腺上皮细胞（MGEC）谱系的ER α CreRFP-T小鼠。RCAS病毒介导的Erbb 2（啮齿动物Her 2同源物）的表达首先产生了相当数量的ER α *RFP* Erbb 2 * 和ER α-RFP-Erbb 2 * MGEC。早期增生主要由ER α *RFP* Erbb 2 * 细胞发展而来，这些病变中的ER α-RFP-Erbb 2 * 细胞很少。随后发展的原位导管癌具有64%的缓慢增殖的ER α *RFP* Erbb 2 * 细胞，15%的快速增殖的ER α-RFP * Erbb 2 * 细胞来源于ER α *RFP* Erbb 2 * 细胞，以及20%的快速增殖的ER α-RFP-Erbb 2 * 细胞。晚期肿瘤主要具有ER α-RFP * Erbb 2 * 和ER α-RFP-Erbb 2 * 细胞，并且仅具有非常小的ER α *RFP* Erbb 2 * 细胞群体。在ER α-RFP * Erbb 2 * 细胞中，GATA 3和FoxA 1表达降低，ER α启动子区甲基化，与ER α表达丧失一致。肺转移瘤主要由ER α-RFP * Erbb 2 * 细胞组成，少数ER α-RFP-Erbb 2 * 细胞，无ER α *RFP* Erbb 2 * 细胞。ER α-RFP * Erbb 2 * 细胞的高转移能力与ERK 1/2活化相关。这些结果表明，缓慢增殖的非转移性ER α *RFP* Erbb 2 * 细胞在肿瘤发生过程中逐渐失去ER α，变成快速增殖的高转移性ER α-RFP * Erbb 2 * 细胞。具有ER α * 起源的ER α-Erbb 2 * BrC比具有ER α-起源的那些ER α-Erbb 2 * BrC更具侵袭性，因此，将来应区分它们并进行不同的治疗。
HER2-positive (HER2*) breast cancers (BrCs) contain approximately equal numbers of ER alpha*HER2* and ER alpha-HER2* cases. An enduring obstacle is the unclear cell lineage-related characteristics of these BrCs. Although ER alpha*HER2* BrCs could lose ER alpha to become ER alpha-HER2* BrCs, direct evidence is missing. To investigate ER alpha dependencies and their implications during BrC growth and metastasis, we generated ER alpha CreRFP-T mice that produce an RFP-marked ER alpha* mammary gland epithelial cell (MGEC) lineage. RCAS virus-mediated expression of Erbb2, a rodent Her2 homolog, first produced comparable numbers of ER alpha*RFP*Erbb2* and ER alpha-RFP-Erbb2* MGECs. Early hyperplasia developed mostly from ER alpha*RFP*Erbb2* cells and ER alpha-RFP-Erbb2* cells in these lesions were rare. The subsequently developed ductal carcinomas in situ had 64% slow-proliferating ER alpha*RFP*Erbb2* cells, 15% fast-proliferating ER alpha-RFP*Erbb2* cells derived from ER alpha*RFP*Erbb2* cells, and 20% fast-proliferating ER alpha-RFP-Erbb2* cells. The advanced tumors had mostly ER alpha-RFP*Erbb2* and ER alpha-RFP-Erbb2* cells and only a very small population of ER alpha*RFP*Erbb2* cells. In ER alpha-RFP*Erbb2* cells, GATA3 and FoxA1 decreased expression and ER alpha promoter regions became methylated, consistent with the loss of ER alpha expression. Lung metastases consisted of mostly ER alpha-RFP*Erbb2* cells, a few ER alpha-RFP-Erbb2* cells, and no ER alpha*RFP*Erbb2* cells. The high metastatic capacity of ER alpha-RFP*Erbb2* cells was associated with ERK1/2 activation. These results show that the slow-proliferating, nonmetastatic ER alpha*RFP*Erbb2* cells progressively lose ER alpha during tumorigenesis to become fast-proliferating, highly metastatic ER alpha-RFP*Erbb2* cells. The ER alpha-Erbb2* BrCs with an ER alpha* origin are more aggressive than those ER alpha-Erbb2* BrCs with an ER alpha- origin, and thus, they should be distinguished and treated differently in the future.