Breast Center, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing, P.R. China.
Berry Oncology Co., Ltd. (Berry Genomics Group), Beijing, P.R. China.
Cancer Res. 2021 May 15;81(10):2600-2611. doi: 10.1158/0008-5472.CAN-20-2123. Epub 2021 Mar 16.
The cell of origin and the development of breast cancer are not fully elucidated in mutation carriers, especially for estrogen receptor (ER)-positive breast cancers. Here, we performed single-cell RNA sequencing (RNA-seq) on 82,122 cells isolated from the breast cancer tissues and adjacent or prophylactic normal breast tissues from four mutation carriers and three noncarriers. Whole-exome sequencing was performed on breast tumors from the four mutation carriers; for validation, bulk RNA-seq was performed on adjacent normal breast tissues from eight additional mutation carriers and 14 noncarriers. Correlation analyses suggested that breast cancers in mutation carriers might originate from luminal cells. The aberrant luminal progenitor cells with impaired differentiation were significantly increased in normal breast tissues in mutation carriers compared with noncarriers. These observations were further validated by the bulk RNA-seq data from additional mutation carriers. These data suggest that the cell of origin of basal-like breast tumors (ER) in mutation carriers might be luminal progenitor cells. The expression of and was decreased in luminal progenitor cells from normal breast tissue in mutation carriers, which might trigger the basal/mesenchymal transition of luminal progenitors and might result in basal-like tumor development. Furthermore, ER luminal tumors might originate from mature luminal cells. Our study provides in-depth evidence regarding the cells of origin of different breast cancer subtypes in mutation carriers. SIGNIFICANCE: Single-cell RNA-seq data indicate that basal-like breast cancer (ER) might originate from luminal progenitors, and ER luminal breast cancer might originate from mature luminal cells in mutation carriers.
在 BRCA1/2 突变携带者中，乳腺癌的起源细胞和发展过程尚未完全阐明，尤其是对于雌激素受体 (ER) 阳性乳腺癌。在此，我们对来自四位 BRCA1/2 突变携带者的乳腺癌组织和相邻或预防性正常乳腺组织中的 82122 个细胞进行了单细胞 RNA 测序 (RNA-seq)。对四位 BRCA1/2 突变携带者的乳腺肿瘤进行了全外显子组测序；为了验证，对另外八位 BRCA1/2 突变携带者和十四位非携带者的相邻正常乳腺组织进行了 bulk RNA-seq。相关性分析表明，BRCA1/2 突变携带者的乳腺癌可能起源于腔细胞。与非携带者相比，BRCA1/2 突变携带者的正常乳腺组织中，异常的腔前体细胞分化受损明显增加。这些观察结果通过来自另外八位 BRCA1/2 突变携带者的 bulk RNA-seq 数据进一步得到了验证。这些数据表明，BRCA1/2 突变携带者的基底样乳腺癌（ER）的起源细胞可能是腔前体细胞。BRCA1/2 突变携带者正常乳腺组织中的腔前体细胞中 和 的表达减少，这可能触发腔前体细胞的基底/间质转化，并导致基底样肿瘤的发展。此外，ER 腔型肿瘤可能起源于成熟的腔细胞。我们的研究为 BRCA1/2 突变携带者不同乳腺癌亚型的起源细胞提供了深入的证据。意义：单细胞 RNA-seq 数据表明，BRCA1/2 突变携带者的基底样乳腺癌（ER）可能起源于腔前体细胞，而 ER 腔型乳腺癌可能起源于成熟的腔细胞。
