Drobysheva Daria, Smith Brittni Alise, McDowell Maria, Guillen Katrin P, Ekiz Huseyin Atakan, Welm Bryan E
Department of Oncological Sciences, University of Utah, 315 South 1400 East, Salt Lake City, UT, 84112, USA.
Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, 825 Northeast 13th Street, Oklahoma City, OK, 73104, USA.
Breast Cancer Res. 2015 Oct 1;17(1):132. doi: 10.1186/s13058-015-0641-9.
Breast cancer exhibits significant molecular, histological, and pathological diversity. Factors that impact this heterogeneity are poorly understood; however, transformation of distinct normal cell populations of the breast may generate different tumor phenotypes. Our previous study demonstrated that the polyomavirus middle T antigen (PyMT) oncogene can establish diverse tumor subtypes when broadly expressed within mouse mammary epithelial cells. In the present study, we assessed the molecular, histological, and metastatic outcomes in distinct mammary cell populations transformed with the PyMT gene.
Isolated mouse mammary epithelial cells were transduced with a lentivirus encoding PyMT during an overnight infection and then sorted into hormone receptor-positive luminal (CD133+), hormone receptor-negative luminal (CD133-), basal, and stem cell populations using the cell surface markers CD24, CD49f, and CD133. Each population was subsequently transplanted into syngeneic cleared mouse mammary fat pads to generate tumors. Tumors were classified by histology, estrogen receptor status, molecular subtype, and metastatic potential to investigate whether transformation of different enriched populations affects tumor phenotype.
Although enriched mammary epithelial cell populations showed no difference in either the ability to form tumors or tumor latency, differences in prevalence of solid adenocarcinomas and squamous, papillary, and sebaceous-like tumors were observed. In particular, squamous metaplasia was observed more frequently in tumors derived from basal and stem cells than in luminal cells. Interestingly, both molecularly basal and luminal tumors developed from luminal CD133+, basal, and stem cell populations; however, luminal CD133- cells gave rise exclusively to molecularly basal tumors. Tumors arising from the luminal CD133-, basal, and stem cell populations were highly metastatic; however, luminal CD133+ cells generated tumors that were significantly less metastatic, possibly due to an inability of these tumor cells to escape the primary tumor site.
Expression of PyMT within different mammary cell populations influences tumor histology, molecular subtype, and metastatic potential. The data demonstrate that luminal CD133+ cells give rise to less metastatic tumors, luminal CD133- cells preferentially establish basal tumors, and the cell of origin for squamous metaplasia likely resides in the basal and stem cell populations.
乳腺癌表现出显著的分子、组织学和病理学多样性。影响这种异质性的因素尚不清楚；然而，乳腺不同正常细胞群体的转化可能产生不同的肿瘤表型。我们之前的研究表明，多瘤病毒中T抗原（PyMT）癌基因在小鼠乳腺上皮细胞中广泛表达时可建立多种肿瘤亚型。在本研究中，我们评估了用PyMT基因转化的不同乳腺细胞群体中的分子、组织学和转移结果。
分离的小鼠乳腺上皮细胞在过夜感染期间用编码PyMT的慢病毒转导，然后使用细胞表面标志物CD24、CD49f和CD133分选成激素受体阳性的管腔细胞（CD133+）、激素受体阴性的管腔细胞（CD133-）、基底细胞和干细胞群体。随后将每个群体移植到同基因清除的小鼠乳腺脂肪垫中以产生肿瘤。通过组织学、雌激素受体状态、分子亚型和转移潜能对肿瘤进行分类，以研究不同富集群体的转化是否影响肿瘤表型。
尽管富集的乳腺上皮细胞群体在形成肿瘤的能力或肿瘤潜伏期方面没有差异，但观察到实体腺癌以及鳞状、乳头状和皮脂腺样肿瘤的发生率存在差异。特别是，与管腔细胞相比，在源自基底细胞和干细胞的肿瘤中更频繁地观察到鳞状化生。有趣的是，分子学上的基底肿瘤和管腔肿瘤均由管腔CD133+、基底细胞和干细胞群体发展而来；然而，管腔CD133-细胞仅产生分子学上的基底肿瘤。源自管腔CD133-、基底细胞和干细胞群体的肿瘤具有高度转移性；然而，管腔CD133+细胞产生的肿瘤转移性明显较低，这可能是由于这些肿瘤细胞无法逃离原发肿瘤部位。
PyMT在不同乳腺细胞群体中的表达影响肿瘤组织学、分子亚型和转移潜能。数据表明，管腔CD133+细胞产生的肿瘤转移性较低，管腔CD133-细胞优先形成基底肿瘤，鳞状化生的起源细胞可能存在于基底细胞和干细胞群体中。
