Emerging evidence suggests that @entity5 arise in stem/progenitor cells. Yet, the requirements for transformation of these primitive cells remains poorly understood. In this study, we have exploited the 'mammosphere' system that selects for primitive mammary stem/progenitor cells to explore their potential and requirements for transformation. Introduction of @entity2235 Early Region and hTERT into mammosphere-derived cells led to the generation of NBLE, an immortalized mammary epithelial cell line. The NBLEs largely comprised of bi-potent progenitors with long-term self-renewal and multi-lineage differentiation potential. Clonal and karyotype analyses revealed the existence of heterogeneous population within NBLEs with varied proliferation, differentiation and sphere-forming potential. Significantly, injection of NBLEs into immunocompromised @entity19 resulted in the generation of invasive @entity420 . Further, these cells harbored a sub-population of @entity1759 (+)/ @entity11707 (-) fraction that alone had sphere- and @entity5 -initiating potential and resembled the @entity0 stem cell gene signature. Interestingly, prolonged in vitro culturing led to their further enrichment. The NBLE cells also showed increased expression of stemness and epithelial to mesenchymal transition markers, deregulated self-renewal pathways, activated DNA-damage response and @entity5 -associated chromosomal aberrations-all of which are likely to have contributed to their tumorigenic transformation. Thus, unlike previous in vitro transformation studies that used adherent, more differentiated @entity1 mammary epithelial cells our study demonstrates that the mammosphere-derived, less-differentiated cells undergo tumorigenic conversion with only two genetic elements, without requiring oncogenic Ras. Moreover, the striking phenotypic and molecular resemblance of the NBLE-generated @entity5 with naturally arising @entity0 supports the notion of a primitive breast cell as the origin for this subtype of @entity0 . Finally, the NBLEs represent a heterogeneous population of cells with striking plasticity, capable of differentiation, self-renewal and tumorigenicity, thus offering a unique model system to study the molecular mechanisms involved with these processes.

Introduction of SV40ER and hTERT into mammospheres generates XXXX cells with stem cell properties.

@entity1 :: ('9606', 'Species') :: ['human'] @entity0 :: ('MESH:D001943', 'Disease') :: ['breast cancer', 'breast adenocarcinomas'] @entity2235 :: ('10633', 'Species') :: ['Simian Virus 40'] @entity5 :: ('MESH:D009369', 'Disease') :: ['tumor', 'cancers', 'cancer', 'tumors'] @entity19 :: ('10090', 'Species') :: ['mice'] @entity11707 :: ('100133941', 'Gene') :: ['CD24'] @entity1759 :: ('960', 'Gene') :: ['CD44'] @entity420 :: ('MESH:D000230', 'Disease') :: ['ductal adenocarcinomas']
@entity0 :: (MESH:D001943,Disease) :: ['breast cancer']
