Stem cell marker prominin‐1 regulates branching morphogenesis, but not regenerative capacity, in the mammary gland

Anderson, Lisa H.; Boulanger, Corinne A.; Smith, Gilbert H.; Carmeliet, Peter; Watson, Christine J.

doi:10.1002/dvdy.22539

Cited by 28 publications

(22 citation statements)

References 35 publications

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“…In normal mammary tissue, CD133/prominin is not a marker for stem cells and seems to regulate ductal branching [25]. Beyond its possible relationship with stemness of tumor cells, CD133 expression in breast cancer significantly correlates with tumor stage, tumor size and occurrence of lymph node metastases [26].…”

Section: Discussionmentioning

confidence: 99%

In triple negative breast tumor cells, PLC-β2 promotes the conversion of CD133high to CD133low phenotype and reduces the CD133-related invasiveness

et al. 2013

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BackgroundBeyond its possible correlation with stemness of tumor cells, CD133/prominin1 is considered an important marker in breast cancer, since it correlates with tumor size, metastasis and clinical stage of triple-negative breast cancers (TNBC), to date the highest risk breast neoplasia.MethodsTo study the correlation between the levels of CD133 expression and the biology of breast-derived cells, CD133low and CD133high cell subpopulations isolated from triple negative MDA-MB-231 cells were compared in terms of malignant properties and protein expression.ResultsHigh expression of CD133 characterizes cells with larger adhesion area, lower proliferation rate and reduced migration speed, indicative of a less undifferentiated phenotype. Conversely, when compared with CD133low cells, CD133high cells show higher invasive capability and increased expression of proteins involved in metastasis and drug-resistance of breast tumors. Among the signalling proteins examined, PLC-β2 expression inversely correlates with the levels of CD133 and has a role in inducing the CD133high cells to CD133low cells conversion, suggesting that, in TNBC cells, the de-regulation of this PLC isoform is responsible of the switch from an early to a mature tumoral phenotype also by reducing the expression of CD133.ConclusionsSince CD133 plays a role in determining the invasiveness of CD133high cells, it may constitute an attractive target to reduce the metastatic potential of TNBC. In addition, our data showing that the forced up-regulation of PLC-β2 counteracts the invasiveness of CD133-positive MDA-MB-231 cells might contribute to identify unexplored key steps responsible for the TNBC high malignancy, to be considered for potential therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

In triple negative breast tumor cells, PLC-β2 promotes the conversion of CD133high to CD133low phenotype and reduces the CD133-related invasiveness

et al. 2013

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“…Mammary progenitor cells differentiate into the luminal epithelial and myoepithelial cells that make up the bilayered structure of the duct (Visvader and Smith 2011; Woodward et al 2005). The differentiation of such progenitors is governed by a multitude of signals from other cells and the extracellular matrix (ECM) (LaBarge et al 2009; Lim et al 2010; Taddei et al 2008; Anderson et al 2011; Liu et al 2006; Dontu et al 2004; Korkaya et al 2009). …”

Section: Introductionmentioning

confidence: 99%

Matrix compliance and RhoA direct the differentiation of mammary progenitor cells

Lui

Lee

Nelson

2011

Biomech Model Mechanobiol

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The regenerative capacity of the mammary gland following post-lactational involution depends on the presence of multipotent stem or progenitor cells. Mammary progenitor cells exist as a quiescent and self-renewing population capable of differentiating into luminal epithelial and myoepithelial cells and generating ductal and alveolar structures. The fate choices of these cells are regulated by several soluble signals as well as their surrounding extracellular matrix. Whereas matrix stiffness has been implicated in organ-specific differentiation of embryonic and mesenchymal stem cells, the effects of substratum compliance on the more limited fate switches typical of tissue-specific progenitor cells is unknown. Here we examined how the mechanical properties of the microenvironment affect the differentiation of mammary progenitor cells. Immortalized human mammary progenitor cells were cultured on synthetic hydrogels of varying stiffness and their self-renewal and fate decisions were quantified. We found that cells cultured on soft substrata differentiated preferentially into luminal epithelial cells, whereas those cultured on stiff substrata differentiated preferentially into myoepithelial cells. Furthermore, pharmacological manipulations of cytoskeletal tension in conjunction with analysis of gene expression revealed that mechanical properties of the microenvironment signal through the small GTPase RhoA and cytoskeletal contractility to modulate the differentiation of mammary progenitor cells. These data suggest that subtle variations in the mechanical compliance of a tissue can direct the fate decisions of its resident progenitor cells.

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“…In contrast, in the normal mammary gland, CD133 is expressed by differentiated ER+ luminal cells, and CD133+ cells exhibit lower regenerative capacity than CD133-cells [206]. Notably, deletion of Prom1 in a knockout mouse model did not impair the regenerative capacity of the normal mammary gland, but did reduce ductal branching during morphogenesis by increasing the ratio of luminal to basal cells [146]. Yet, in the NKI 295 data set, PROM1 expression levels were found to be lower in ERα+ tumors than in ERα-tumors [146].…”

Section: Discussionmentioning

confidence: 93%

“…Notably, deletion of Prom1 in a knockout mouse model did not impair the regenerative capacity of the normal mammary gland, but did reduce ductal branching during morphogenesis by increasing the ratio of luminal to basal cells [146]. Yet, in the NKI 295 data set, PROM1 expression levels were found to be lower in ERα+ tumors than in ERα-tumors [146]. The association of HIF-1α and PROM1 expression in ER-breast cancers is not surprising, given that hypoxia is a potent stimulator of ERα degradation [207,208].…”

Section: Discussionmentioning

confidence: 96%

“…Three markers of secretory differentiation were analyzed, adipose differentiation-related protein (ADRP; also known as adipophilin), ß-casein (CSN2) and whey acidic protein (WAP). Whereas ß-casein is one of the earliest markers of differentiation induced by pregnancy hormones, Wap and Adrp are expressed during later stages of differentiation [146,147]. Antibodies to ADRP have also been used to immunostain the surface of CLD produced by differentiated MEC [145].…”

Section: -2f)mentioning

confidence: 99%

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Identification of Novel HIF1A Target Genes That Regulate Tumor Progression and Metastasis

Peacock¹

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DEDICATION ABSTRACTHypoxia is a hallmark of most solid tumors. In response to hypoxic stress tumor cells adapt by regulating survival, metabolism and angiogenesis. The heterodimeric Hypoxia-Inducible Factor (HIF) transcription factors are the master regulators of this response. HIFs play key roles in many critical aspects of cancer biology including angiogenesis, stem cell maintenance, metabolic reprogramming, invasion, metastasis and resistance to radiation therapy and chemotherapy. Overexpression of HIF-1α and HIF-2α has been documented in multiple human cancers and HIF-1α protein is over-expressed in ~30% of primary breast tumors and ~70% of metastases, which independently correlates with poor prognosis and decreased survival in patients. A precise role for HIF-2α in breast cancer is still being elucidated.Our lab has established primary mammary tumor epithelial cells (MTECs) from late stage carcinomas originating in PyMT+; Hif1a floxed mice. These MTECs were exposed to either Adenovirus-beta-gal or -Cre to create wild-type (WT) and knockout (KO) cells, respectively. Deletion of HIF-1 activity reduced primary tumor growth by ~60% and the formation of lung macrometastases originating from mammary fat pad tumors by >90%. In addition, deletion of Hif1a reduced mammary tumorsphere formation efficiency (TSE) in vitro and tumor initiating cell (TIC) frequency in vivo. In contrast, in triple negative models of breast cancer, knockdown of HIF1A had the opposite phenotype, increasing TSE in vitro and increased primary mammary tumor growth in vivo. ITGA6 (CD49f) was identified as one HIF-1α-dependent cancer stem cell marker that enriches for both primary mammary tumor growth and metastasis to the lung. Microarray profiling conducted to identify genes differentially expressed between PyMT WT and KO cells and end-stage WT and KO tumors revealed several genes that were down-regulated in both data sets in response to deletion of Hif1a. One mRNA of particular interest, creatine kinase brain isoform (Ckb) was down-regulated in KO cells >100 fold and >2 fold in end-stage tumors. Transplantation of Ckb knockdown (KD) PyMT cells to the mammary fat pad delayed initiation of palpable tumors by >30 days. When cells were introduced into the circulation via tail vein injection, 20% of mice injected with Ckb KD cells developed lung metastases whereas 100% of mice injected with WT cells developed metastases. Likewise, when mice injected with WT PyMT cells were treated daily with a CKB chemical inhibitor, cyclocreatine (cCr), lungs of vehicle treated (saline) mice were almost completely covered with surface metastases, while lungs of cCr treated mice contained very few metastases.Overall, our data show that HIF-1α strongly promotes mammary tumor initiation, progression and metastasis, in part through regulation of TIC activity. Metastasis is the major cause of mortality in breast cancer patients. Further characterization of the distinct roles of HIF-1α versus HIF-2α in breast cancer and metastasis, and genes downstream of the HIFs, suc...

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Stem cell marker prominin‐1 regulates branching morphogenesis, but not regenerative capacity, in the mammary gland

Cited by 28 publications

References 35 publications

In triple negative breast tumor cells, PLC-β2 promotes the conversion of CD133high to CD133low phenotype and reduces the CD133-related invasiveness

In triple negative breast tumor cells, PLC-β2 promotes the conversion of CD133high to CD133low phenotype and reduces the CD133-related invasiveness

Matrix compliance and RhoA direct the differentiation of mammary progenitor cells

Identification of Novel HIF1A Target Genes That Regulate Tumor Progression and Metastasis

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