Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.
Oncogene. 2011 Oct 27;30(43):4399-409. doi: 10.1038/onc.2011.147. Epub 2011 May 2.
Progenitor cells are considered an important cell of origin of human malignancies. However, there has not been any single gene that can define mammary bipotential progenitor cells, and as such it has not been possible to use genetic methods to introduce oncogenic alterations into these cells in vivo to study tumorigenesis from them. Keratin 6a is expressed in a subset of mammary luminal epithelial cells and body cells of terminal end buds. By generating transgenic mice using the Keratin 6a (K6a) gene promoter to express tumor virus A (tva), which encodes the receptor for avian leukosis virus subgroup A (ALV/A), we provide direct evidence that K6a(+) cells are bipotential progenitor cells, and the first demonstration of a non-basal location for some biopotential progenitor cells. These K6a(+) cells were readily induced to form mammary tumors by intraductal injection of RCAS (an ALV/A-derived vector) carrying the gene encoding the polyoma middle T antigen. Tumors in this K6a-tva line were papillary and resembled the normal breast-like subtype of human breast cancer. This is the first model of this subtype of human tumors and thus may be useful for preclinical testing of targeted therapy for patients with normal-like breast cancer. These observations also provide direct in vivo evidence for the hypothesis that the cell of origin affects mammary tumor phenotypes.
祖细胞被认为是人类恶性肿瘤的重要起源细胞。然而，目前还没有任何一个单一的基因可以定义乳腺双潜能祖细胞，因此，不可能使用遗传方法将致癌改变引入这些细胞中，从而在体内研究它们的肿瘤发生。角蛋白 6a 在乳腺腔上皮细胞和终末芽体的体细胞亚群中表达。通过使用角蛋白 6a（K6a）基因启动子生成转基因小鼠来表达肿瘤病毒 A（tva），该病毒编码禽白血病病毒亚群 A（ALV/A）的受体，我们提供了直接证据表明 K6a(+)细胞是双潜能祖细胞，这也是首次证明一些双潜能祖细胞位于非基底位置。通过向这些 K6a(+)细胞内注射携带编码多瘤病毒中间 T 抗原基因的 RCAS（一种源自 ALV/A 的载体），很容易诱导它们形成乳腺肿瘤。在这个 K6a-tva 系中，肿瘤呈乳头状，类似于人类乳腺癌的正常乳腺样亚型。这是这种人类肿瘤亚型的第一个模型，因此可能有助于对具有正常样乳腺癌的患者进行靶向治疗的临床前测试。这些观察结果还为这样的假说提供了直接的体内证据，即起源细胞会影响乳腺肿瘤表型。
