Isoform-Specific Ras Activation and Oncogene Dependence during MYC- and Wnt-Induced Mammary Tumorigenesis

Jang, Joanne; Boxer, Robert; Chodosh, Lewis A.

doi:10.1128/mcb.00404-06

Cited by 59 publications

(56 citation statements)

References 43 publications

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“…1A). We also confirmed previous studies (11)(12)(13) showing that bitransgenic animals with an inducible (human) MYC transgene (TOM;MTB) developed solitary mammary tumors; in our cohort the median latency was 26 weeks (Fig. 1 B).…”

Section: G12dsupporting

confidence: 92%

“…Our choice of Myc and Ras transgenes for these studies was influenced in part by these early observations, in part by subsequent work implicating spontaneous mutations of Kras genes in the maintenance of tumors induced by regulated Myc (11)(12)(13) and in part by the availability of doxycycline-inducible transgenes encoding Myc and mutant Kras (7,8).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Oncogene cooperation in tumor maintenance and tumor recurrence in mouse mammary tumors induced by Myc and mutant Kras

Podsypanina

Politi

Beverly

et al. 2008

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

121

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Most, if not all, cancers are composed of cells in which more than one gene has a cancer-promoting mutation. Although recent evidence has shown the benefits of therapies targeting a single mutant protein, little attention has been given to situations in which experimental tumors are induced by multiple cooperating oncogenes. Using combinations of doxycycline-inducible and constitutive Myc and mutant Kras transgenes expressed in mouse mammary glands, we show that tumors induced by the cooperative actions of two oncogenes remain dependent on the activity of a single oncogene. Deinduction of either oncogene individually, or both oncogenes simultaneously, led to partial or complete tumor regression. Prolonged remission followed deinduction of Kras G12D in the context of continued Myc expression, deinduction of a MYC transgene with continued expression of mutant Kras produced modest effects on life extension, whereas simultaneous deinduction of both MYC and Kras G12D transgenes further improved survival. Disease relapse after deinduction of both oncogenes was associated with reactivation of both oncogenic transgenes in all recurrent tumors, often in conjunction with secondary somatic mutations in the tetracycline transactivator transgene, MMTVrtTA, rendering gene expression doxycycline-independent. These results demonstrate that tumor viability is maintained by each gene in a combination of oncogenes and that targeted approaches will also benefit from combination therapies.inducible ͉ mammary gland ͉ ras R ecent successes in the treatment of several human cancers using agents directed against the products of single oncogenes (1) and the prospect of many more such agents becoming available (2) raise important questions about long-term outcomes of interfering with certain mutations in cancer cells. Should targeted therapies be directed against all of the genetic damage in a cancer cell? Or do cancer cells display a differential dependence on mutations, and can that differential be used to select the most potent targeted therapies?Experimental murine models of human cancer that depend on regulated oncogenic transgenes mimic hypothetical therapeutic situations in human cancers, for which highly effective targeted therapies might be used to block the action of one or more oncogenes. These models are indispensable for testing the effects of blocking two common human oncogenes, Myc and Kras, for which no effective therapies currently exist. By using this approach, tumor regression in response to oncogene withdrawal has been observed across multiple tumor types induced by either Myc or mutant Kras transgenes-lymphomas, leukemias, insulinomas, lung, bone, liver, and breast tumors (3, 4). However, inactivation of the same oncogene in different tumor types produced a range of long-term outcomes, from complete cure to invariable relapse.To reduce the effects of genetic variability on tumor regression and long-term remission after selective oncogene inactivation, we took advantage of the cooperative behavior of Myc and mutant Kra...

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Section: G12dsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Oncogene cooperation in tumor maintenance and tumor recurrence in mouse mammary tumors induced by Myc and mutant Kras

Podsypanina

Politi

Beverly

et al. 2008

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

121

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show abstract

“…In support of this theory, previous studies illustrated that tumors with both Myc and Ras expression regress upon deinduction of Ras, but not Myc (22). Additional work has shown that Myc tumors that regress upon deinduction of the Myc transgene only do so in the absence of Ras (23). Taken together, this suggests that there is a requirement for Ras activation in Myc tumors, but upon Ras activation, the nature of the tumor is sufficiently changed so that the role for Myc is altered.…”

Section: Discussionsupporting

confidence: 50%

Genetic heterogeneity of Myc-induced mammary tumors reflecting diverse phenotypes including metastatic potential

Andrechek

Cardiff

Chang

et al. 2009

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

120

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Human cancers result from a complex series of genetic alterations, resulting in heterogeneous disease states. Dissecting this heterogeneity is critical for understanding underlying mechanisms and providing opportunities for therapeutics matching the complexity. Mouse models of cancer have generally been used to reduce this complexity and focus on the role of single genes. Nevertheless, our analysis of tumors arising in the MMTV-Myc model of mammary carcinogenesis reveals substantial heterogeneity, seen in both histological and expression phenotypes. One contribution to this heterogeneity is the substantial frequency of activating Ras mutations. Additionally, we show that these Myc-induced mammary tumors exhibit even greater heterogeneity, revealed by distinct histological subtypes as well as distinct patterns of gene expression, than many other mouse models of tumorigenesis. Two of the major histological subtypes are characterized by differential patterns of cellular signaling pathways, including ␤-catenin and Stat3 activities. We also demonstrate that one of the MMTV-Myc mammary tumor subgroups exhibits metastatic capacity and that the signature derived from the subgroup can predict metastatic potential of human breast cancer. Together, these data reveal that a combination of histological and genomic analyses can uncover substantial heterogeneity in mammary tumor formation and therefore highlight aspects of tumor phenotype not evident in the population as a whole.breast ͉ cancer ͉ genomics ͉ mouse

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“…Interestingly, mutations in Kras were also recovered from mammary tumors of MMTV-Myc transgenic mice. Apparently, however, there is specificity in the activation of Ras isoforms in mammary tumors because, in contrast to the Myc case, a high percentage of cancers induced either by constitutively active Wnt1 (24/46; 52%) 26 or Dox-regulatable Wnt1 (54/95; 57%) 27 were found to harbor exclusively or predominantly Hras1 activating mutations (Hras1:Kras = 18:1).…”

Section: Myc and Mouse Mammary Tumorsmentioning

confidence: 99%

Notch, Myc and Breast Cancer

Efstratiadis

Szabolcs²,

Klinakis³

2007

Cell Cycle

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Isoform-Specific Ras Activation and Oncogene Dependence during MYC- and Wnt-Induced Mammary Tumorigenesis

Cited by 59 publications

References 43 publications

Oncogene cooperation in tumor maintenance and tumor recurrence in mouse mammary tumors induced by Myc and mutant Kras

Oncogene cooperation in tumor maintenance and tumor recurrence in mouse mammary tumors induced by Myc and mutant Kras

Genetic heterogeneity of Myc-induced mammary tumors reflecting diverse phenotypes including metastatic potential

Notch, Myc and Breast Cancer

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