Mammary epithelial reconstitution with gene-modified stem cells assigns roles to Stat5 in luminal alveolar cell fate decisions, differentiation, involution, and mammary tumor formation

Vida Vafaizadeh, Petra Klemmt, Christian Brendel, Kristoffer Weber, Carmen Doebele, Kara Louise Britt, Manuel Grez, Boris Fehse, Sylvane Desrivieres, Bernd Groner

Research output: Contribution to journalArticleResearchpeer-review

71 Citations (Scopus)

Abstract

The mammary gland represents a unique model system to study gene functions in adult stem cells. Mammary stem cells (MaSCs) can regenerate a functional epithelium upon transplantation into cleared fat pads. We studied the consequences of distinct genetic modifications of MaSCs on their repopulation and differentiation ability. The reconstitution of ductal trees was used as a stem cell selection procedure and the nearly quantitative lentiviral infection efficiency of the primary mammary epithelial cells (MECs) rendered the enrichment of MaSCs prior to their transplantation unnecessary. The repopulation frequency of transduced MaSCs was nearly 100 in immunodeficient recipients and the resulting transgenic ducts homogeneously expressed the virally encoded fluorescent marker proteins. Transplantation of a mixture of MECs, expressing different fluorescent proteins, resulted in a distinct pattern of ductal outgrowths originating from a small number of individually transduced MaSCs. We used genetically modified MECs to define multiple functions of Stat5 during mammary gland development and differentiation. Stat5-downregulation in MaSCs did not affect primary ductal outgrowth, but impaired side-branching and the emergence of mature alveolar cells from luminal progenitors during pregnancy. Conversely, the expression of a constitutively active variant of Stat5, cS5-F, caused epithelial hyperproliferation, thickening of the ducts and precocious, functional alveoli formation in virgin mice. Expression of cS5-F also prevented involution and caused the formation of ER(+)PR(+) adenocarcinomas. The tumors expressed activated Stat5 and Stat3 and contained a small fraction of CD44(+) cells, possibly indicative of cancer stem cells (CSCs).
Original languageEnglish
Pages (from-to)928 - 938
Number of pages11
JournalStem Cells
Volume28
Issue number5
DOIs
Publication statusPublished - 2010

Cite this