Development of mammary luminal progenitor cells is controlled by the transcription factor STAT5A

Abstract

Mammary alveologenesis is abrogated in the absence of the transcription factors STAT5A/5B, which mediate cytokine signaling. To reveal the underlying causes for this developmental block, we studied mammary stem and progenitor cells. While loss of STAT5A/5B did not affect the stem cell population and its ability to form mammary ducts, luminal progenitors were greatly reduced and unable to form alveoli during pregnancy. Temporally controlled expression of transgenic STAT5A in mammary epithelium lacking STAT5A/5B restored the luminal progenitor population and rescued alveologenesis in a reversible fashion in vivo. Thus, STAT5A is necessary and sufficient for the establishment of luminal progenitor cells.Supplemental material is available at http://www.genesdev.org.

Analysis of Brca1-deficient mouse mammary glands reveals reciprocal regulation of Brca1 and c-kit

“…Error bars represent s.e., and significance was determined by Student's t-test with ***Po0.001, **0.001oPo0.01. mice, which exhibit an expansion of the CD61 þ progenitor population during puberty and pregnancy (Asselin-Labat et al, 2007), and Elf5 À/À and Stat5a À/À mice, which show an increase in these progenitors at mid-pregnancy (Oakes et al, 2008;Yamaji et al, 2009). Interestingly, non-parous precancerous tissues from BRCA1 mutation carriers harbour an aberrant luminal progenitor population (Lim et al, 2009), whereas young virgin mice do not (Figure 1d).…”

“…Mouse models displaying defects in these processes have also been very useful, for example, Gata-3, Elf-5 and Stat5a knockout mice have helped define the cellular events involved in the development of luminal and secretory cells, respectively (Asselin-Labat et al, 2007;Oakes et al, 2008;Yamaji et al, 2009), whereas PrlR and Gal knockout mice have shed light on the molecular events associated with the secretory activation stage of lactation (Naylor et al, 2005).…”

Transcription factor regulatory networks in mammary epithelial development and tumorigenesis

“…A clear relationship exists between STAT5A and Elf-5 during the commitment and differentiation of luminal alveolar cells. Recent work demonstrates that deletion of STAT5A/5B in the mammary glands results in a severe defect in lobuloalveolar differentiation without effects on ductal outgrowth (Yamaji et al, 2009). Similarly, Elf-5 À/À glands are also capable of normal ductal elongation and branching morphogenesis but fail to undergo proper lobuloalveolar differentiation (Oakes et al, 2008;Choi et al, 2009).…”

“…Although these factors are clearly necessary for the proper development of the virgin mammary gland ductal tree and subsequent development during pregnancy, it is not yet clear how these proteins control the specification of distinct cell types within the emerging differentiation hierarchy of the mammary gland. In this respect, recent work has begun to focus on elucidating the roles and interactions of several key transcription factors during normal mammary epithelial differentiation of specific mammary epithelial populations Asselin-Labat et al, 2007;Oakes et al, 2008;Choi et al, 2009;Yamaji et al, 2009). In addition to terminal differentiation, another set of transcription factors are involved in the involution phase of mammary gland development, notably STAT3.…”

“…To better understand the nature of this developmental block, a conditional STAT5A/5B allele was generated to permit mammary gland-specific ablation of both these key transcription factors following mammary epithelial expression of Cre recombinase (Yamaji et al, 2009). Mammary epithelial disruption of both STAT5A and STAT5B did not negatively impact the mammary stem cell population or their ability to contribute to normal ductal development.…”