ID4 controls mammary stem cells and marks breast cancers with a stem cell-like phenotype

Junankar, Simon; Baker, Laura A.; Roden, Daniel; Nair, Radhika; Elsworth, Benjamin; Gallego‐Ortega, David; Lacaze, Paul; Cazet, Aurélie; Nikolić, Iva; Teo, Wee Siang; Yang, Jessica; McFarland, Andrea; Harvey, Kate; Naylor, Matthew J.; Lakhani, Sunil R.; Simpson, Peter T.; Raghavendra, Ashwini; Saunus, Jodi M.; Madore, Jason; Kaplan, Warren; Ormandy, Christopher J.; Millar, Ewan K.A.; O’Toole, Sandra A.; Yun, Kyuson; Swarbrick, Alexander

doi:10.1038/ncomms7548

Cited by 54 publications

(109 citation statements)

References 65 publications

(93 reference statements)

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“…Both genes are stem cell markers, prompting speculation that NOTCH3 may function in basal breast cancer to maintain an undifferentiated state. ID4 has also been described as a master regulator of the basal lineage (42), suggesting that NOTCH3, through control of a downstream transcriptional network that includes ID4, may regulate the same cell fate. Extending this rationale to the malignant state, it is tempting to speculate that NOTCH3 may help maintain a basal tumor subtype and oppose establishment of luminal or other subtypes.…”

Section: Discussionmentioning

confidence: 99%

Constitutive NOTCH3 Signaling Promotes the Growth of Basal Breast Cancers

Choy¹,

Hagenbeek²,

Solon³

et al. 2017

Cancer Research

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Notch ligands signal through one of four receptors on neighboring cells to mediate cell-cell communication and control cell fate, proliferation, and survival. Although aberrant Notch activation has been implicated in numerous malignancies, including breast cancer, the importance of individual receptors in distinct breast cancer subtypes and the mechanisms of receptor activation remain unclear. Using a novel antibody to detect active NOTCH3, we report here that NOTCH3 signals constitutively in a panel of basal breast cancer cell lines and in more than one third of basal tumors. Selective inhibition of individual ligands revealed that this signal does not require canonical ligand induction. A NOTCH3 antagonist antibody inhibited growth of basal lines, whereas a NOTCH3 agonist antibody enhanced the transformed phenotype in vitro and in tumor xenografts. Transcriptomic analyses generated a Notch gene signature that included Notch pathway components, the oncogene c-Myc, and the mammary stem cell regulator Id4. This signature drove clustering of breast cancer cell lines and tumors into the common subtypes and correlated with the basal classification. Our results highlight an unexpected ligand-independent induction mechanism and suggest that constitutive NOTCH3 signaling can drive an oncogenic program in a subset of basal breast cancers.

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Section: Discussionmentioning

confidence: 99%

Constitutive NOTCH3 Signaling Promotes the Growth of Basal Breast Cancers

Choy¹,

Hagenbeek²,

Solon³

et al. 2017

Cancer Research

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“…Members of the family of inhibitors of differentiation (ID) also contribute to stem cell activity and differentiation choices between basal and luminal cells. ID4 is exclusively expressed in basal cells and suppresses luminal differentiation in an in vitro system (29). Overexpression of ID1 in mammary tissue of transgenic mice results in the preferential expansion of basal cells and ductal hyperplasia (30).…”

mentioning

confidence: 99%

Histone Demethylase KDM6A Controls the Mammary Luminal Lineage through Enzyme-Independent Mechanisms

Yoo

Kang

et al. 2016

Molecular and Cellular Biology

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“…There is also evidence that the expression of CEACAM1 and ID1 are inversely related in going from normal to malignant transformation in the breast (47), possibly implicating ID4 in the regulation of both ID1 and ID2. Finally, the oncogenic role of ID4 in triple negative breast cancer (11) and promotion of angiogenesis in glioblastoma argues that expression of ID4 is not always beneficial. Because ID4 functions as an inhibitor of transcription factors, it may promote cancer by inhibiting normal genes, or inhibit cancer by inhibiting oncogenes.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, ID4 has been shown to play an important role in breast, prostate, and colon (9) cancers, all tissues that show high CEACAM1 expression in normal and low expression in malignant tissue. On the other hand, ID4 is expressed in a subset of mammary basal cells as a marker of stemness, acting upstream of Notch signaling (11). In the study by Junankar et al (11), up-regulation of ID4 was detected in one-half of triple negative breast cancers where its inhibition by RNAi halted cell division.…”

mentioning

confidence: 99%

“…On the other hand, ID4 is expressed in a subset of mammary basal cells as a marker of stemness, acting upstream of Notch signaling (11). In the study by Junankar et al (11), up-regulation of ID4 was detected in one-half of triple negative breast cancers where its inhibition by RNAi halted cell division. ID4 is also highly expressed in glioblastoma multiforme promoting angiogenesis by regulating high levels of the matrix protein GLA (12).…”

mentioning

confidence: 99%

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Induction of Lumen Formation in a Three-dimensional Model of Mammary Morphogenesis by Transcriptional Regulator ID4

Shively

2016

Journal of Biological Chemistry

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Concomitant loss of lumen formation and cell adhesion protein CEACAM1 is a hallmark feature of breast cancer. In a threedimensional culture model, transfection of CEACAM1 into MCF7 breast cells can restore lumen formation by an unknown mechanism. ID4, a transcriptional regulator lacking a DNA binding domain, is highly up-regulated in CEACAM1-transfected MCF7 cells, and when down-regulated with RNAi, abrogates lumen formation. Conversely, when MCF7 cells, which fail to form lumena in a three-dimensional culture, are transfected with ID4, lumen formation is restored, demonstrating that ID4 may substitute for CEACAM1. After showing the ID4 promoter is hypermethylated in MCF7 cells but hypomethylated in MCF/ CEACAM1 cells, ID4 expression was induced in MCF7 cells by agents affecting chromatin remodeling and methylation. Mechanistically, CaMK2D was up-regulated in CEACAM1-transfected cells, effecting phosphorylation of HDAC4 and its sequestration in the cytoplasm by the adaptor protein 14-3-3. CaMK2D also phosphorylates CEACAM1 on its cytoplasmic domain and mutation of these phosphorylation sites abrogates lumen formation. Thus, CEACAM1 is able to maintain the active transcription of ID4 by an epigenetic mechanism involving HDAC4 and CaMK2D, and the same kinase enables lumen formation by CEACAM1. Because ID4 can replace CEACAM1 in parental MCF7 cells, it must act downstream from CEACAM1 by inhibiting the activity of other transcription factors that would otherwise prevent lumen formation. This overall mechanism may be operative in other cancers, such as colon and prostate, where the down-regulation of CEACAM1 is observed.Lumen formation, a central feature of mammary morphogenesis, is lost during mammary tumorigenesis, starting with filling in the lumen with cancer cells in ductal carcinoma in situ (1) and becoming more evident in invasive solid tumors (2). Identification of the molecules that change during this process and the underlying mechanisms causing these changes are major goals of breast cancer research. Among the many molecules identified so far, CEACAM1 stands out as a luminal expressed protein that is rapidly down-regulated in both ductal carcinoma in situ (3) and invasive breast cancer (2). Not surprisingly, luminal expression of CEACAM1 occurs throughout ductal tissues such as the liver, digestive and urogenital tract, and prostate, and its loss upon malignant transformation is one of the earliest events observed (4). To study its role in lumen formation, we originally placed MCF10F, a cell line that expresses CEACAM1, in a three-dimensional culture system pioneered by Bissell and co-workers (5), and observed lumen formation with CEACAM1 at the luminal surface (3). When its expression was blocked by antisense, anti-CEACAM1 antibody, or peptides derived from the N terminus of CEACAM1, lumen formation was abrogated, demonstrating that its expression played a central role in the complex process of lumenogenesis (3). As a next step, we demonstrated that MCF7 breast cancer cells that fail to express CEACAM1 o...

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ID4 controls mammary stem cells and marks breast cancers with a stem cell-like phenotype

Cited by 54 publications

References 65 publications

Constitutive NOTCH3 Signaling Promotes the Growth of Basal Breast Cancers

Constitutive NOTCH3 Signaling Promotes the Growth of Basal Breast Cancers

Histone Demethylase KDM6A Controls the Mammary Luminal Lineage through Enzyme-Independent Mechanisms

Induction of Lumen Formation in a Three-dimensional Model of Mammary Morphogenesis by Transcriptional Regulator ID4

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