Of Mice and Myc: c-Myc and Mammary Tumorigenesis

Jamerson, Matthew H.; Johnson, Michael D.; Dickson, Robert B.

doi:10.1023/b:jomg.0000023586.69263.0b

Cited by 56 publications

(33 citation statements)

References 52 publications

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“…MYC is a well-known suppressor of TGF-β signaling (36) and is amplified in up to 52% of breast cancer specimens, depending on the study. Tumors that do not harbor an MYC amplification often overexpress MYC protein via additional mechanisms (36)(37)(38)(39). RAS mutations are surprisingly infrequent in breast cancer (<5%) relative to other cancers (50% of colon and thyroid cancers and 90% of pancreatic cancers).…”

Section: Discussionmentioning

confidence: 99%

TGF-β signaling engages an ATM-CHK2-p53–independent RAS-induced senescence and prevents malignant transformation in human mammary epithelial cells

Cipriano¹,

Kan²,

Graham³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Oncogene-induced senescence (OIS), the proliferative arrest engaged in response to persistent oncogene activation, serves as an important tumor-suppressive barrier. We show here that finite lifespan human mammary epithelial cells (HMEC) undergo a p16/ RB-and p53-independent OIS in response to oncogenic RAS that requires TGF-β signaling. Suppression of TGF-β signaling by expression of a dominant-negative TGF-β type II receptor, use of a TGF-β type I receptor inhibitor, or ectopic expression of MYC permitted continued proliferation upon RAS expression. Surprisingly, unlike fibroblasts, shRNA-mediated knockdown of ATM or CHK2 was unable to prevent RAS-mediated OIS, arguing that the DNA damage response is not required for OIS in HMEC. Abrogation of TGF-β signaling not only allowed HMEC lacking p53 to tolerate oncogenic RAS but also conferred the capacity for anchorage-independent growth. Thus, the OIS engaged after dysregulated RAS expression provides an early barrier to malignant progression and is mediated by TGF-β receptor activation in HMEC. Understanding the mechanisms that initiate and maintain OIS in epithelial cells may provide a foundation for future therapies aimed at reengaging this proliferative barrier as a cancer therapy. (ii) constitutive growth signaling, (iii) unlimited replication potential, and (iv) invasive potential (1). Early studies using normal mouse cells indicated that a limited set of genetic manipulations could confer neoplastic potential (2). However, normal human cells have been more difficult to transform to malignancy, indicative of their more stringent tumor-suppressive pathways. Extensive study of cultured human mammary epithelial cells (HMEC) has identified two senescence barriers. One involves the stress-associated induction of the cyclin-dependent kinase inhibitor p16 before attaining critically short telomeres. This stasis barrier can be overcome by inhibiting p16, allowing continued proliferation, which results in agonescence, a proliferative barrier mediated by telomere depletion (3). Additionally, the ability of dysregulated oncogenic signaling to induce senescence in human cells has implicated oncogene-induced senescence (OIS) as an important tumor-suppressive barrier. A number of recent studies have demonstrated the physiological relevance of OIS in human tumorigenesis and in vivo tumor mouse models (4). Additionally, the presence of senescent cells in benign but not advanced tumors argues that OIS serves as an early tumorsuppressive barrier that needs to be dismantled for full oncogenic progression (4). In human fibroblasts, OIS could be bypassed by disabling p16 or molecular components of the DNA damage response (DDR), including ATM, CHK2, or p53, before RAS, MOS, or STAT5 overexpression (5-9). However, OIS in HMEC has been shown to be independent of p53 and the p16-RB pathway after oncogenic RAF-1 expression (10). The contrasting responses between epithelial and fibroblast cells argue that the signaling networks responsible for OIS have tissue specificity. Indeed, fibrob...

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Section: Discussionmentioning

confidence: 99%

TGF-β signaling engages an ATM-CHK2-p53–independent RAS-induced senescence and prevents malignant transformation in human mammary epithelial cells

Cipriano¹,

Kan²,

Graham³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…37,39 These crucial cell culture based findings laid foundation to concept that apoptosis represents a major block to c-Myc-dependent tumorigenesis and this concept has now been validated in many different transgenic c-Myc mouse models. [42][43][44] Bax and Bcl-2 have antagonistic roles in regulation of the mitochondrial apoptosis pathway (Box 2). Thus, one might expect that loss of Bax has similar tumor promoting consequences as Bcl-2 (or Bcl-x L ) overexpression 42 in context of c-Myc-dependent tumorigenesis.…”

Section: Myc Primes Activation Of the Mitochondrial Pathway Of Apoptosismentioning

confidence: 99%

c-Myc Blazing a Trail of Death: Coupling of the Mitochondrial and Death Receptor Apoptosis Pathways by c-Myc

Nieminen¹,

Partanen²,

Klefström³

2007

Cell Cycle

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TRAIL ligand induces selectively apoptosis in tumor cells by binding to two death receptors (DR4 and DR5) and holds promise as a potential therapeutic agent against cancer. While it has been known for long time that TRAIL receptors are commonly expressed in wide variety of normal tissues, it is not well understood why TRAIL kills tumor cells but leaves normal cells unharmed. The prototypic oncogene c-Myc promotes the cell cycle and simultaneously primes activation of the Bcl-2 family controlled mitochondria apoptosis pathway. A striking reflection of the c-Myc-dependent apoptotic sensitization is the dramatic c-Myc-induced vulnerability of cells to TRAIL and other death receptor ligands. Here we summarize the recent findings regarding the death mechanisms of TRAIL/TRAIL receptor system and the connection of c-Myc to the mitochondrial apoptosis pathway, focusing on our work that couples c-Myc via Bak to the TRAIL death receptor pathway. Finally, we present a mitochondria-priming model to explain how c-Myc-Bak interaction amplifies the TRAIL-induced caspase 8-Bid pathway to induce full-blown apoptosis. We discuss the implications of these findings for understanding the selective cytotoxicity of TRAIL and for the therapeutic exploitation of the death receptor pathway. DeAth receptors: Guilty of MurDer beyonD reAsonAble Doubt?TNF and TRAIL. Tumor necrosis factor-alpha (TNF) is a founding member of large TNF-family of proteins and was once considered in cancer research community as nothing less than phenomenal protein due to its ability to exert cytotoxic effects towards about one third of cancer cell lines without harming non-transformed cell lines. 1,2 However, the systemic administration of recombinant TNF caused severe side effects, including hemorrhagic necrosis, cachexia, fever and shock in laboratory animals and this precluded systemically administered TNF from clinical use. 3,4 The observed side effects were not caused by any rampant cell deaths triggered by the death ligand TNF, but rather they reflected effects of the cytokine TNF, which was found to play a key role in regulation of immunity and inflammation responses. 5 Indeed, inhibitors of TNF show promise in treatment of inflammation-linked disorders such as rheumatoid arthritis. 6 Discovery of TNF-related apoptosis-inducing ligand (TRAIL/Apo2L) and its two TNF receptor 1 related and death domain containing signaling receptors DR4 and DR5 brought death receptors back to attention of cancer field since TRAIL performed well where TNF had failed. TRAIL was demonstrated to exhibit TNF-like selective apoptotic activity towards tumor cells in vitro and in vivo and importantly, unlike TNF, TRAIL has been well tolerated in preclinical toxicity assays. 7,8 These findings quickly prompted several TRAIL based cancer therapies, which are currently in phase I and II clinical trials. 9 TRAIL receptors DR4 and DR5 are constitutively expressed in wide variety of tissues 10,11 (see also NCBI UniGene's EST ProfileViewer) and the ligated receptors can induce apopt...

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“…MMTV-ErbB2 female mice were obtained from the laboratory of Dr Mike Ruppert (UAB) and mammary tumors, and uninvolved mammary glands, were excised from these mice. MMTV-c-Myc mice have been described before (18). All mice were housed and cared for in AAALACaccredited facilities in accordance with guidelines established by the NIH.…”

Section: Methodsmentioning

confidence: 99%

High Cks1 expression in transgenic and carcinogen-initiated mammary tumors is not always accompanied by reduction in p27Kip1

Westbrook

Ramanathan²,

Isayeva³

et al. 2009

Int J Oncol

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Abstract. Cks1 plays an essential role in SCFSkp2 -mediated ubiquitination, and consequently turnover, of the cdk2 inhibitor and tumor supressor p27 Kip1 . High Cks1 expression is associated with aggressive breast tumors and correlates with low p27Kip1 levels in some cases, although it is also an independent prognostic marker for survival, and provides predictive information in addition to that provided by p27 Kip1 alone. In this report we demonstrate that Cks1 protein and mRNA are elevated to very high levels in mammary tumors initiated by erbB2, c-myc and polyoma middle-T (PyMT) in transgenic mice, whereas Cks1 protein is hardly detectable in the normal mammary epithelium. Cks1 is also highly upregulated in rat mammary tumors initiated by methylnitrosourea (MNU). Despite high levels of Cks1 expression, p27 Kip1 levels were not reduced, and were in fact slightly higher in mammary tumors initiated by erbB2, PyMT and MNU. In contrast mammary tumors from MMTV-c-myc mice did exhibit low p27Kip1 and higher levels of Skp2. Together, these data suggest that deregulated Cks1 expression might play roles in oncogene and carcinogen-initiated mammary tumorigenesis independent of p27 Kip1 turnover in certain tumors. Stable overexpression of Cks1 in human breast carcinoma MCF-7 cells did not significantly reduce p27 Kip1 expression, although it conferred resistance to Faslodex (ICI 182780)-mediated inhibition of colony outgrowth in these cells. In contrast, Cks1-depleted MCF-7 cells formed fewer colonies in estrogen-containing medium. Therefore, our studies also suggest that Cks1 levels regulate the responsiveness of ER + breast cancers to estrogens and anti-estrogens.

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Of Mice and Myc: c-Myc and Mammary Tumorigenesis

Cited by 56 publications

References 52 publications

TGF-β signaling engages an ATM-CHK2-p53–independent RAS-induced senescence and prevents malignant transformation in human mammary epithelial cells

TGF-β signaling engages an ATM-CHK2-p53–independent RAS-induced senescence and prevents malignant transformation in human mammary epithelial cells

c-Myc Blazing a Trail of Death: Coupling of the Mitochondrial and Death Receptor Apoptosis Pathways by c-Myc

High Cks1 expression in transgenic and carcinogen-initiated mammary tumors is not always accompanied by reduction in p27Kip1

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