Redefining the Expression and Function of the Inhibitor of Differentiation 1 in Mammary Gland Development

Nair, Radhika; Junankar, Simon; O’Toole, Sandra A.; Shah, Jaynish S.; Borowsky, Alexander D.; Bishop, J. Michael; Swarbrick, Alexander

doi:10.1371/journal.pone.0011947

Cited by 14 publications

(11 citation statements)

References 23 publications

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“…Recent immunohistochemical analysis of a variety of tumor types supports the idea that the oncogenic properties of Id1 are largely mediated by its expression in stromal tissue rather than in tumor cells and that its major role may be in promoting tumor angiogenesis (50,61). However, our studies clearly demonstrate robust and widespread expression of Id1 in the nuclei of intestinal tumor cells.…”

Section: Discussionsupporting

confidence: 68%

Protein Kinase Cα Signaling Regulates Inhibitor of DNA Binding 1 in the Intestinal Epithelium

Fang¹,

Pysz²,

Curry³

et al. 2011

Journal of Biological Chemistry

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Increasing evidence supports a role for PKC␣ in growth arrest and tumor suppression in the intestinal epithelium. In contrast, the Id1 transcriptional repressor has pro-proliferative and tumorigenic properties in this tissue. Here, we identify Id1 as a novel target of PKC␣ signaling. Using a highly specific antibody and a combined morphological/biochemical approach, we establish that Id1 is a nuclear protein restricted to proliferating intestinal crypt cells. A relationship between PKC␣ and Id1 was supported by the demonstration that (a) down-regulation of Id1 at the crypt/villus junction coincides with PKC␣ activation, and (b) loss of PKC␣ in intestinal tumors is associated with increased levels of nuclear Id1. Manipulation of PKC␣ activity in IEC-18 nontransformed intestinal crypt cells determined that PKC␣ suppresses Id1 mRNA and protein via an Erk-dependent mechanism. PKC␣, but not PKC␦, also inhibited Id1 expression in colon cancer cells. Id1 was found to regulate cyclin D1 levels in IEC-18 and colon cancer cells, pointing to a role for Id1 suppression in the antiproliferative/tumor suppressive activities of PKC␣. Notably, Id1 expression was elevated in the intestinal epithelium of PKC␣-knock-out mice, confirming that PKC␣ regulates Id1 in vivo. A wider role for PKC␣ in control of inhibitor of DNA binding factors is supported by its ability to downregulate Id2 and Id3 in IEC-18 cells, although their suppression is more modest than that of Id1. This study provides the first demonstrated link between a specific PKC isozyme and inhibitor of DNA binding factors, and it points to a role for a PKC␣ 3 Erk ٜ Id1 3 cyclin D1 signaling axis in the maintenance of intestinal homeostasis.The intestinal epithelium is a continually self-renewing tissue, organized into well defined proliferative and functional compartments (1). Maintenance of tissue integrity relies on tight control of the balance between proliferative activity, differentiation, and apoptosis. Both positive and negative growth regulatory signaling pathways have been implicated in orchestrating the renewal process in this tissue, and disruption of these pathways and/or their downstream targets results in various diseases, including cancer. Increasing evidence points to the PKC enzyme system as a key regulator of intestinal homeostasis (2-6). PKC is a family of phospholipid-dependent serine-threonine kinases, consisting of at least 10 isozymes that act as central players in signal transduction. Members of the family can have tumor promoting (e.g. PKC␤II, -⑀, and -) or tumor suppressive (e.g. PKC␣ and -␦) activity, dependent on the isozyme and tissue context (2,5,7,8). Although several PKC isozymes have been implicated in the regulation of intestinal homeostasis (e.g. PKC␣, -␤II, -␦, -⑀, and -), increasing evidence points to PKC␣ as a key negative regulator of proliferation and tumorigenesis in this tissue (4, 9, 10).PKC␣ is activated precisely at the point of growth arrest in the crypts of both the small intestine and colon (11, 12). Consistent with a role i...

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Section: Discussionsupporting

confidence: 68%

Protein Kinase Cα Signaling Regulates Inhibitor of DNA Binding 1 in the Intestinal Epithelium

Fang¹,

Pysz²,

Curry³

et al. 2011

Journal of Biological Chemistry

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“…While the roles of individual Id proteins are not well understood, current data support a role for Id2 in both the development of lactation (43) and in the maintenance of a differentiated and non-invasive phenotype (33, 44). Although the specific role of Id1 in mammary gland development and in neoplastic transformation is presently unclear (45), the cooperation of Id1 and Id3 in Triple Negative BC (ER-, PR-, Her2-) and in the progression and proliferation of lung metastasis has been identified (46). We uncovered highly divergent expression of Id proteins during HC11 differentiation and parallel divergence in mRNA expression during mouse mammary gland development in vivo that are consistent with these observations.…”

Section: Discussionmentioning

confidence: 99%

Contribution of Xanthine Oxidoreductase to Mammary Epithelial and Breast Cancer Cell Differentiation In Part Modulates Inhibitor of Differentiation-1

Fini

Monks

Farabaugh

et al. 2011

Molecular Cancer Research

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Loss of Xanthine oxidoreductase (XOR) has been linked to aggressive breast cancer (BC) in vivo and to BC cell aggressiveness in vitro. In the present study we hypothesized that the contribution of XOR to the development of the normal mammary gland may underlie its capacity to modulate BC. We contrasted in vitro and in vivo developmental systems by differentiation marker and microarray analyses. Human BC microarray was used for clinical outcome studies. The role of XOR in differentiation and proliferation was examined in human BC cells and in a mouse xenograft model. Our data show that XOR was required for functional differentiation of mammary epithelial cells both in vitro and in vivo. Poor XOR expression was observed in a mouse ErbB2 BC model, and pharmacologic inhibition of XOR increased BC tumor burden in mouse xenograft. MRNA microarray analysis of human BC revealed that low XOR expression was significantly associated with time to tumor relapse. The opposing expression of XOR and Id1 during HC11 differentiation and mammary gland development suggested a potential functional relationship. While overexpression of Id1 inhibited HC11 differentiation and XOR expression, XOR itself modulated expression of Id1 in differentiating HC11 cells. Overexpression of XOR both inhibited Id1 induced proliferation and stimulated differentiation of Heregulinβ1 treated human BC cells. These results demonstrate that XOR is an important functional component of differentiation whose diminished expression contributes to BC aggressiveness, and they support XOR as both a BC biomarker and a target for pharmacologic activation in therapeutic management of aggressive BC.

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“…In the mammary gland, ID1 is not detectable in luminal epithelium during any phase of development (Uehara et al, 2003;Nair et al, 2010). Id2 is expressed in mammary epithelial cells and is important for terminal differentiation in cultured mammary epithelial cells and for mammary gland alveologenesis during pregnancy (Mori et al, 2000;Parrinello et al, 2001;Itahana et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

ID4 regulates mammary gland development by suppressing p38MAPK activity

et al. 2011

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SUMMARYThe ID family of helix-loop-helix proteins regulates cell proliferation and differentiation in many different developmental pathways, but the functions of ID4 in mammary development are unknown. We report that mouse Id4 is expressed in cap cells, basal cells and in a subset of luminal epithelial cells, and that its targeted deletion impairs ductal expansion and branching morphogenesis as well as cell proliferation induced by estrogen and/or progesterone. We discover that p38MAPK is activated in Id4-null mammary cells. p38MAPK is also activated following siRNA-mediated Id4 knockdown in transformed mammary cells. This p38MAPK activation is required for the reduced proliferation and increased apoptosis in Id4-ablated mammary glands. Therefore, ID4 promotes mammary gland development by suppressing p38MAPK activity.KEY WORDS: ID4, p38MAPK (MAPK14, MAPK11), Mammary development, Breast cancer, Wnt, Mouse ID4 regulates mammary gland development by suppressing p38MAPK activity

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Redefining the Expression and Function of the Inhibitor of Differentiation 1 in Mammary Gland Development

Cited by 14 publications

References 23 publications

Protein Kinase Cα Signaling Regulates Inhibitor of DNA Binding 1 in the Intestinal Epithelium

Protein Kinase Cα Signaling Regulates Inhibitor of DNA Binding 1 in the Intestinal Epithelium

Contribution of Xanthine Oxidoreductase to Mammary Epithelial and Breast Cancer Cell Differentiation In Part Modulates Inhibitor of Differentiation-1

ID4 regulates mammary gland development by suppressing p38MAPK activity

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