Delineating the Epithelial Hierarchy in the Mouse Mammary Gland

Asselin-Labat, Marie Liesse; Vaillant, François; Shackleton, Mark; Bouras, Toula; Lindeman, Geoffrey J.; Visvader, Jane E.

doi:10.1101/sqb.2008.73.020

Cited by 41 publications

(44 citation statements)

References 97 publications

(100 reference statements)

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“…Advances in molecular analysis of primary tumors make clear that different subtypes of human breast cancer exist (30). Increasing evidence suggests that the molecular subtype of a given breast cancer may be a reflection of the cell type from which that cancer originates (20,(31)(32)(33). Therefore, it is critical to understand the signaling pathways that define the epithelial ontogeny of the mammary gland and how these pathways may be used within cancers that arise from each cell type.…”

Section: Discussionmentioning

confidence: 99%

The receptor tyrosine kinase ErbB3 maintains the balance between luminal and basal breast epithelium

Balko¹,

Miller

Morrison³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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ErbB3 harbors weak kinase activity, but strongly activates downstream phosphatidylinositol 3-kinase/Akt signaling through heterodimerization with and activation by other ErbB receptor tyrosine kinases. We report here that ErbB3 loss in the luminal mammary epithelium of mice impaired Akt and MAPK signaling and reduced luminal cell proliferation and survival. ERBB3 mRNA expression levels were highest in luminal mammary populations and lowest in basal cell/stem cell populations. ErbB3 loss in mammary epithelial cells shifted gene expression patterns toward a mammary basal cell/stem cell signature. ErbB3 depletion-induced gene expression changes were rescued upon activation of Akt and MAPK signaling. Interestingly, proliferation and expansion of the mammary basal epithelium (BE) occurred upon ErbB3 targeting in the luminal epithelium, but not upon its targeting in the BE. Multiple cytokines, including interleukin 6, were induced upon ErbB3 depletion in luminal epithelium cells, which increased growth of BE cells. Taken together, these results suggest that ErbB3 regulates the balance of differentiated breast epithelial cell types by regulating their growth and survival through autocrine-and paracrinesignaling mechanisms.A berrant regulation of the ErbB family of receptor tyrosine kinases (RTKs) and their ligands is common in human cancers (1-4). This family consists of four members: HER1/ErbB1/ EGFR (epidermal growth factor receptor), HER2/ErbB2/Neu, HER3/ErbB3, and HER4/ErbB4. Except for ErbB3, which has weak kinase activity, the ErbB RTKs exhibit dimerization-induced phosphorylation and catalytic activation. In response to ligand binding, ErbBs form homodimers and heterodimers with other ErbB coreceptors. ErbB3 relies on transphosphorylation by heterodimeric partners to induce signal transduction (5-7).ErbB RTKs are required for breast development, although each receptor bears a unique spatiotemporal expression pattern. ErbB2 loss in the mammary epithelium delays ductal elongation during puberty and disorganizes cells within terminal end buds (TEBs) (8-10). EGFR and ErbB4 are not required for mammary ductal development. Rather, EGFR is expressed in the basal epithelium (BE) and in the mammary stroma, and ErbB4 is necessary for milk production (11,12). Although classical knockout of mouse ErbB3 results in embryonic lethality (13), transplant experiments showed that ErbB3 drives growth of the mammary epithelium during puberty (8). Although the mechanism(s) by which ErbB2 and ErbB3 regulate growth of the ductal epithelium are currently unknown, such knowledge will impact our understanding of the earliest events contributing to the formation of ErbB2/HER2-amplified breast cancers, which account for 20-30% of all breast cancers. ErbB3-ErbB2 heterodimers are the most potent oncogenic ErbB-signaling pair due in part to strong ErbB3-induced phosphatidylinositol 3-kinase (PI3K) activation in response to ErbB3 tyrosine phosphorylation at six PI3K interaction motifs (14,15).To understand the role of ErbB3 in mammary gland dev...

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Section: Discussionmentioning

confidence: 99%

The receptor tyrosine kinase ErbB3 maintains the balance between luminal and basal breast epithelium

Balko¹,

Miller

Morrison³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…The actively proliferating cap/basal cells in TEBs are potential progenitors for myoepithelial cells, while the body cells within the TEB are the precursors of luminal cells. 4 Upon reproduction, the pouched structures at the end of lobules further develop into milk-producing alveoli structures. Thus, mammary gland development in mice is accompanied by extensive branching morphogenesis and activation of pluripotent or bipotent stem/progenitor cells.…”

Section: Introductionmentioning

confidence: 99%

CD151 represses mammary gland development by maintaining the niches of progenitor cells

et al. 2014

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Tetraspanin CD151 interacts with laminin-binding integrins (i.e., a3b1, a6b1 and a6b4) and other cell surface molecules to control diverse cellular and physiological processes, ranging from cell adhesion, migration and survival to tissue architecture and homeostasis. Here, we report a novel role of CD151 in maintaining the branching morphogenesis and activity of progenitor cells during the pubertal development of mammary glands. In contrast to the disruption of laminin-binding integrins, CD151 removal in mice enhanced the tertiary branching in mammary glands by 2.4-fold and the number of terminal end buds (TEBs) by 30%, while having minimal influence on either primary or secondary ductal branching. Consistent with these morphological changes are the skewed distribution of basal/ myoepithelial cells and a 3.2-fold increase in proliferating Ki67-positive cells. These novel observations suggest that CD151 impacts the branching morphogenesis of mammary glands by upregulating the activities of bipotent progenitor cells. Indeed, our subsequent analyses indicate that upon CD151 removal the proportion of CD24 Hi CD49f Low progenitor cells in the mammary gland increased by 34%, and their proliferating and differentiating activities were significantly upregulated. Importantly, fibronectin, a pro-branching extracellular matrix (ECM) protein deposited underlying mammary epithelial or progenitor cells, increased by >7.2-fold. Moreover, there was a concomitant increase in the expression and nuclear distribution of Slug, a transcription factor implicated in the maintenance of mammary progenitor cell activities. Taken together, our studies demonstrate that integrin-associated CD151 represses mammary branching morphogenesis by controlling progenitor cell activities, ECM integrity and transcription program.

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“…The isolation of epithelial stem cells from both mouse (Shackleton et al, 2006;Stingl et al, 2006a) and human (Ginestier et al, 2007;Eirew et al, 2008;Lim et al, 2009) mammary glands, and the assessment of their ability to regenerate this tissue in vivo, has begun to build the framework for a differentiation hierarchy in the adult mammary gland (Stingl et al, 2006b;Molyneux et al, 2007;Asselin-Labat et al, 2008;Visvader, 2009). In the mouse mammary gland, a single stem cell that is characterized as CD29 hi /CD49f hi / CD24 þ /mod /Sca-1 À can give rise to all epithelial cell types required to produce a functional mammary gland and possesses self-renewal properties (Shackleton et al, 2006;Stingl et al, 2006a).…”

Section: Introductionmentioning

confidence: 99%

Transcription factor regulatory networks in mammary epithelial development and tumorigenesis

Siegel

Muller

2010

Oncogene

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The mouse mammary gland is composed of three epithelial cell types, which include ductal, alveolar and myoepithelial cells. A hierarchy in which the mammary stem cell compartment gives rise to progressively restricted progenitors that ultimately form the luminal (ductal and alveolar) and myoepithelial lineages is now emerging. Although very little is known about the mechanisms controlling the differentiation of the myoepithelial cell lineage, a growing body of work reveals that the luminal cell fate is specified by a network of transcription factors. The precise roles of specific transcription factors in promoting differentiation of luminal progenitors into ductal or alveolar cells are now being elucidated. This review will discuss the importance of these recent observations and place them within the context of other transcription factor networks involved in mammary gland development and tumorigenesis.

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Delineating the Epithelial Hierarchy in the Mouse Mammary Gland

Cited by 41 publications

References 97 publications

The receptor tyrosine kinase ErbB3 maintains the balance between luminal and basal breast epithelium

The receptor tyrosine kinase ErbB3 maintains the balance between luminal and basal breast epithelium

CD151 represses mammary gland development by maintaining the niches of progenitor cells

Transcription factor regulatory networks in mammary epithelial development and tumorigenesis

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