c-Myc affects mRNA translation, cell proliferation and progenitor cell function in the mammary gland

Stoelzle, Tina; Schwarb, Patrick; Trumpp, Andreas; Hynes, Nancy E.

doi:10.1186/1741-7007-7-63

Cited by 34 publications

(39 citation statements)

References 90 publications

(123 reference statements)

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“…3, left panel). 37,38 Levels of MYC that are supraphysiological in the basal cells studied here might therefore be tolerated in luminal cells. It is tempting to speculate hat rare premalignant cells could survive the MYC-induced cell identity switch and these cancerous cells with new luminal identity will eventually benefit from MYC/ MIZ1 pro-survival functions.…”

Section: Discussionmentioning

confidence: 99%

MYC-induced apoptosis in mammary epithelial cells is associated with repression of lineage-specific gene signatures

et al. 2016

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Apoptosis caused by deregulated MYC expression is a prototype example of intrinsic tumor suppression. However, it is still unclear how supraphysiological MYC expression levels engage specific sets of target genes to promote apoptosis. Recently, we demonstrated that repression of SRF target genes by MYC/MIZ1 complexes limits AKT-dependent survival signaling and contributes to apoptosis induction. Here we report that supraphysiological levels of MYC repress gene sets that include markers of basal-like breast cancer cells, but not luminal cancer cells, in a MIZ1-dependent manner. Furthermore, repressed genes are part of a conserved gene signature characterizing the basal subpopulation of both murine and human mammary gland. These repressed genes play a role in epithelium and mammary gland development and overlap with genes mediating cell adhesion and extracellular matrix organization. Strikingly, acute activation of oncogenic MYC in basal mammary epithelial cells is sufficient to induce luminal cell identity markers. We propose that supraphysiological MYC expression impacts on mammary epithelial cell identity by repressing lineage-specific target genes. Such abrupt cell identity switch could interfere with adhesiondependent survival signaling and thus promote apoptosis in pre-malignant epithelial tissue.

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Section: Discussionmentioning

confidence: 99%

MYC-induced apoptosis in mammary epithelial cells is associated with repression of lineage-specific gene signatures

et al. 2016

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“…Extracts were prepared from murine mammary glands and polysome fractionation was carried out essentially as described previously 58,59 with some modifications. Glands from virgin, late-pregnant (d16.5-17.0) or lactating (2 dL and 4 dL) mice (n = 2 for each time-point) were flash-frozen in liquid nitrogen and ground to a homogeneous powder.…”

Section: Cycloheximide Pulse-chase Experiments Sorted Mammary Luminamentioning

confidence: 99%

EGF-mediated induction of Mcl-1 at the switch to lactation is essential for alveolar cell survival

Rios

Pal

et al. 2015

Nat Cell Biol

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Expansion and remodelling of the mammary epithelium requires a tight balance between cellular proliferation, differentiation and death. To explore cell survival versus cell death decisions in this organ, we deleted the pro-survival gene Mcl-1 in the mammary epithelium. Mcl-1 was found to be essential at multiple developmental stages including morphogenesis in puberty and alveologenesis in pregnancy. Moreover, Mcl-1-deficient basal cells were virtually devoid of repopulating activity, suggesting that this gene is required for stem cell function. Profound upregulation of the Mcl-1 protein was evident in alveolar cells at the switch to lactation, and Mcl-1 deficiency impaired lactation. Interestingly, EGF was identified as one of the most highly upregulated genes on lactogenesis and inhibition of EGF or mTOR signalling markedly impaired lactation, with concomitant decreases in Mcl-1 and phosphorylated ribosomal protein S6. These data demonstrate that Mcl-1 is essential for mammopoiesis and identify EGF as a critical trigger of Mcl-1 translation to ensure survival of milk-producing alveolar cells.

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“…Myc over-expression in the luminal layer of the mouse mammary gland leads to unscheduled lobulo-alveolar development and tumorigenesis [16,17]. Myc deletion from the differentiated luminal cells affects milk secretion and moderately reduces the repopulating capacity of the mammary epithelium as evaluated by transplantation of tissue fragments [18]. However, neither the functions of Myc in the mammary basal epithelial compartment nor the effects of Myc deletion on distinct mammary stem/progenitor populations have been studied so far.…”

Section: Introductionmentioning

confidence: 99%

The Proto-Oncogene Myc Is Essential for Mammary Stem Cell Function

et al. 2012

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The mammary epithelium comprises two major cell lineages: basal and luminal. Basal cells (BCs) isolated from the mammary epithelium and transplanted into the mouse mammary fat pad cleared from the endogenous epithelium regenerate the mammary gland, strongly suggesting that the basal epithelial compartment harbors a long-lived cell population with multipotent stem cell potential. The luminal cell layer is devoid of the regenerative potential, but it contains cells with clonogenic capacity, the luminal progenitors. Mammary BCs and luminal progenitors express high levels of the transcription factor Myc. Here, we show that deletion of Myc from mammary basal epithelial cells led to impaired stem cell self-renewal as evaluated by limiting dilution and serial transplantation assays. Luminal progenitor population was significantly diminished in mutant epithelium suggesting control by the BC layer. Colony formation assay performed with isolated BCs showed that clonogenic capacity was abolished by Myc deletion. Moreover, transplanted BCs depleted of Myc failed to produce epithelial outgrowths. Stimulation with ovarian hormones estrogen (E) and progesterone (P) partially rescued the repopulation capacity of Myc-depleted BCs; however, the Myc-deficient mammary epithelium developed in response to E/P treatment lacked stem and progenitor cells. This study provides the first evidence that in the mammary gland, Myc has an essential nonredundant function in the maintenance of the self-renewing multipotent stem cell population responsible for the regenerative capacity of the mammary epithelium and is required downstream from ovarian hormones, for the control of mammary stem and progenitor cell functions.

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c-Myc affects mRNA translation, cell proliferation and progenitor cell function in the mammary gland

Cited by 34 publications

References 90 publications

MYC-induced apoptosis in mammary epithelial cells is associated with repression of lineage-specific gene signatures

MYC-induced apoptosis in mammary epithelial cells is associated with repression of lineage-specific gene signatures

EGF-mediated induction of Mcl-1 at the switch to lactation is essential for alveolar cell survival

The Proto-Oncogene Myc Is Essential for Mammary Stem Cell Function

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