Paracrine signaling through the epithelial estrogen receptor α is required for proliferation and morphogenesis in the mammary gland

Mallepell, Sonia; Krust, Andrée; Chambon, Pierre; Brisken, Cathrin

doi:10.1073/pnas.0510974103

Cited by 374 publications

(355 citation statements)

References 53 publications

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“…It may be that forced c-Kit expression prevented differentiation and this stopped normal outgrowths from developing (for example, by preventing the appearance of functionally mature luminal Sca-1 þ ER þ cells required for the paracrine interactions necessary for ductal extension) (Mallepell et al, 2006). Consistent with this, downregulation of c-Kit expression was observed when c-Kit þ cells were cultured under conditions that generate an in vivo-like morphology.…”

Section: Discussionmentioning

confidence: 88%

c-Kit is required for growth and survival of the cells of origin of Brca1-mutation-associated breast cancer

et al. 2011

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BRCA1 mutation-associated breast cancer originates in oestrogen receptor-alpha-negative (ER À ) progenitors in the mammary luminal epithelium. These cells also express high levels of the Kit gene and a recent study demonstrated a correlation between Brca1 loss and Kit over-expression in the mammary epithelium. However, the functional significance of c-Kit expression in the mammary gland is unknown. To address this, c-Kit À and c-Kit þ mammary epithelial subsets were isolated by flow cytometry, characterised for expression of lineage-specific cell markers and functionally analysed by in vitro colony forming and in vivo transplantation assays. The results confirm that the majority of luminal ER À progenitors are c-Kit þ , but also that most stem cells and the differentiated cell populations are c-Kit À . A subset of c-Kit þ cells with high proliferative potential was found in the luminal ER þ population, however, suggesting the existence of a distinct luminal ER þ progenitor cell type. Analysis of mouse Brca1 mammary tumours demonstrated that they expressed Kit and its downstream effector Lyn at levels comparable to the most strongly c-Kit þ luminal ER À progenitors. Consistent with c-Kit being a progenitor cell marker, in vitro threedimensional differentiation of c-Kit þ cells resulted in a loss of c-Kit expression, whereas c-Kit over-expression prevented normal differentiation in vivo. Furthermore, c-Kit was a functional marker of proliferative potential, as c-Kit inhibition by short hairpin knockdown prevented normal epithelial growth and caused cells to undergo apoptosis. Therefore, c-Kit defines distinct progenitor populations in the mammary epithelium and is critical for mammary progenitor survival and proliferation. Importantly, c-Kit is only the second mammary epithelial stem/progenitor marker to be shown to have a functional role in the mammary epithelium and the first marker to be shown to be required for progenitor cell function. The c-Kit signalling network has potential as a target for therapy and/or prevention in BRCA1-associated breast cancer.

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Section: Discussionmentioning

confidence: 88%

c-Kit is required for growth and survival of the cells of origin of Brca1-mutation-associated breast cancer

et al. 2011

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“…Therefore, in ERα-null mice, mammary glands are normal before puberty [34]. However, after the onset of puberty, terminal end buds remain absent, and ducts fail to invade the fat pad beyond the nipple, which indicate the strong influence of ERα in mammary gland development [35]. Recent studies also established that ERα not only regulates ductal morphogenesis during puberty, but is also involved in alveologenesis during pregnancy and lactation [36].…”

Section: E2 Signaling In Mammary Gland Developmentmentioning

confidence: 99%

RETRACTED ARTICLE: Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy

Zhou

Qiao

Shetty

et al. 2013

Cell. Mol. Life Sci.

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Estrogen and estrogen receptors (ERs) are critical regulators of breast epithelial cell proliferation, differentiation, and apoptosis. Compromised signaling vis-à-vis the estrogen receptor is believed © Springer Basel 2013 yow4@pitt.edu. ), which predicts for response to endocrine-based therapy; however, innate or acquired resistance to endocrinebased drugs remains a serious challenge. The complexity of regulation for estrogen signaling coupled with the crosstalk of other oncogenic signaling pathways is a reason for endocrine therapy resistance. Alternative strategies that target novel molecular mechanisms are necessary to overcome this current and urgent gap in therapy. A thorough analysis of estrogen-signaling regulation is critical. In this review article, we will summarize current insights into the regulation of estrogen signaling as related to breast carcinogenesis and breast cancer therapy. NIH Public Access

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“…Initial embryonic tissue recombination studies suggested that ERα was solely required within the stromal compartment [60], whereas adult tissue transplants suggested that it was needed in both the stromal and epithelial compartments [61]. More recent results, however, indicate that these former studies were hampered by incomplete ERα inactivation and instead suggest that ERα is only required within the mammary epithelium [62]. Nevertheless, ERα-null mammary epithelial cells can still contribute to all portions of the developing mammary tree if they are rescued by nearby wild-type cells, thus indicating that ERα affects mammary development in a non-cell-autonomous manner.…”

Section: What Cues Act Upstream Of the Adam17-areg-egfr Axis?mentioning

confidence: 99%

The ADAM17–amphiregulin–EGFR Axis in Mammary Development and Cancer

Sternlicht

Sunnarborg

2008

J Mammary Gland Biol Neoplasia

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In order to fulfill its function of producing and delivering sufficient milk to newborn mammalian offspring, the mammary gland first has to form an extensive ductal network. As in all phases of mammary development, hormonal cues elicit local intra-and inter-cellular signaling cascades that regulate ductal growth and differentiation. Among other things, ductal development requires the epidermal growth factor receptor (EGFR), its ligand amphiregulin (AREG), and the transmembrane metalloproteinase AD-AM17, which can cleave and release AREG from the cell surface so that it may interact with its receptor. Tissue recombination and transplantation studies demonstrate that EGFR phosphorylation and ductal development proceed only when ADAM17 and AREG are expressed on mammary epithelial cells and EGFR is present on stromal cells, and that local administration of soluble AREG can rescue the development of ADAM17-deficient transplants. Thus proper mammary morphogenesis requires the ADAM17-mediated release of AREG from ductal epithelial cells, the subsequent activation of EGFR on stromal cells, and EGFR-dependent stromal responses that in return elicit a new set of epithelial responses, all culminating in the formation of a fully functional ductal tree. This, however, raises new issues concerning what may act upstream, downstream or in parallel with the ADAM17-AREG-EGFR axis, how it may become hijacked or corrupted during the onset and evolution of cancer, and how such ill effects may be confronted.

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Paracrine signaling through the epithelial estrogen receptor α is required for proliferation and morphogenesis in the mammary gland

Cited by 374 publications

References 53 publications

c-Kit is required for growth and survival of the cells of origin of Brca1-mutation-associated breast cancer

c-Kit is required for growth and survival of the cells of origin of Brca1-mutation-associated breast cancer

RETRACTED ARTICLE: Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy

The ADAM17–amphiregulin–EGFR Axis in Mammary Development and Cancer

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