Luminal epithelial cells within the mammary gland can produce basal cells upon oncogenic stress

Oncogene (2016) 35, 14611467 2016 Macmillan Publishers Limited All rights reserved 0950-9232/16

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SHORT COMMUNICATION

Luminal epithelial cells within the mammary gland can produce basal cells upon oncogenic stress

SM Hein1,2, S Haricharan2, AN Johnston2, MJ Toneff1, JP Reddy1,3, J Dong1,2, W Bu1,2 and Y Li1,2

In the normal mammary gland, the basal epithelium is known to be bipotent and can generate either basal or luminal cells, whereas the luminal epithelium has not been demonstrated to contribute to the basal compartment in an intact and normally developed mammary gland. It is not clear whether cellular heterogeneity within a breast tumor results from transformation of bipotent basal cells or from transformation and subsequent basal conversion of the more differentiated luminal cells. Here we used a retroviral vector to express an oncogene specically in a small number of the mammary luminal epithelial cells and tested their potential to produce basal cells during tumorigenesis. This in-vivo lineage-tracing work demonstrates that luminal cells are capable of producing basal cells on activation of either polyoma middle T antigen or ErbB2 signaling. These ndings reveal the plasticity of the

luminal compartment during tumorigenesis and provide an explanation for cellular heterogeneity within a cancer.

Oncogene (2016) 35, 14611467; doi:http://dx.doi.org/10.1038/onc.2015.206

Web End =10.1038/onc.2015.206 ; published online 22 June 2015

INTRODUCTIONHuman breast tumors take many years to form and are usually clonal.1,2 The majority of human breast cancers are comprised primarily of cells resembling the luminal layer of the normal mammary epithelium and are thought to originate in these cells. However, some human breast tumors also harbor both luminaland basal-like cells, or have a basal-like expression prole.3,4

Therefore, heterogeneous tumors must be derived from basal cells that become luminal cells, or vice versa.

In early mammary development, both the luminal and basal epithelial compartments are generated from bipotent progenitors expressing markers of both lineages.5,6 After birth, although it is controversial whether basal cells can give rise to luminal cells in an unperturbed mammary gland, they retain the capability of regenerating a complete ductal tree after isolation and transplantation into an epithelia-cleared fat pad.6,7 However, luminal cells have been repeatedly demonstrated to be lineage-restricted and incapable of generating basal cells in either the intact mammary gland or upon transplantation.59 It is unclear...