Consequences of Epithelial or Stromal TGFβ1 Depletion in the Mammary Gland

Nguyen, David H.; Martinez-Ruiz, Haydeliz; Barcellos‐Hoff, Mary Helen

doi:10.1007/s10911-011-9218-0

Cited by 11 publications

(18 citation statements)

References 65 publications

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“…Four highly differentially expressed regulators were identified: FGF2, ANGPT2, IL5, and TGFβ1 (Table 1). These 4, all tumor promoters (22, 31–33), were predicted to be significantly inhibited in old mice. Both FGF2 (31) and ANGPT2 (32) are angiogenesis-associated factors, whereas IL5 is involved in angiogenesis and immune response (34, 35) and TGFβ1 in many functions including vascular development and angiogenesis (36).…”

Section: Resultsmentioning

confidence: 98%

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Host Age Is a Systemic Regulator of Gene Expression Impacting Cancer Progression

et al. 2015

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Aging is the major determinant of cancer incidence, which, in turn, is likely dictated in large part by processes that influence the progression of early subclinical (occult) cancers. However, there is little understanding of how aging informs changes in aggregate host signaling that favor cancer progression. In this study, we provide direct evidence that aging can serve as an organizing axis to define cancer progression-modulating processes. As a model system to explore this concept, we employed adolescent (68 days), young adult (143 days), middle-aged (551 days), and old (736 days) C57BL/6 mice as syngeneic hosts for engraftment of Lewis lung cancer to identify signaling and functional processes varying with host age. Older hosts exhibited dysregulated angiogenesis, metabolism, and apoptosis, all of which are associated with cancer progression. TGFβ1, a central player in these systemic processes, was downregulated consistently in older hosts. Our findings directly supported the conclusion of a strong host age dependence in determining the host tumor control dynamic. Furthermore, our results offer initial mechanism-based insights into how aging modulates tumor progression in ways that may be actionable for therapy or prevention.

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Section: Resultsmentioning

confidence: 98%

“…TGFβ1, involved in a considerable number of carcinogenesis steps (22, 23), was found to be key. Employing a systems approach, the cohort-dependent tumor growth dynamics were further linked to the underlying biology using a modified version of the widely used tumor growth model of Hahnfeldt and colleagues (24).…”

Section: Introductionmentioning

confidence: 99%

Host Age Is a Systemic Regulator of Gene Expression Impacting Cancer Progression

et al. 2015

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“…There is also considerable evidence for increased levels of activated TGF-␤ in preneoplastic lesions (74), and these are primarily restricted to the epithelium (75), where it has been shown to accelerate breast cancer progression and metastasis in animal models (76). The overexpression of eIF4E clearly does not activate latent TGF-␤.…”

Section: Discussionmentioning

confidence: 99%

Eukaryotic Translation Initiation Factor 4E Is a Feed-Forward Translational Coactivator of Transforming Growth Factor β Early Protransforming Events in Breast Epithelial Cells

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Barcellos-Hoff

et al. 2015

Molecular and Cellular Biology

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Eukaryotic translation initiation factor 4E (eIF4E) is overexpressed early in breast cancers in association with disease progression and reduced survival. Much remains to be understood regarding the role of eIF4E in human cancer. We determined, using immortalized human breast epithelial cells, that elevated expression of eIF4E translationally activates the transforming growth factor ␤ (TGF-␤) pathway, promoting cell invasion, a loss of cell polarity, increased cell survival, and other hallmarks of early neoplasia. Overexpression of eIF4E is shown to facilitate the selective translation of integrin ␤1 mRNA, which drives the translationally controlled assembly of a TGF-␤ receptor signaling complex containing ␣3␤1 integrins, ␤-catenin, TGF-␤ receptor I, E-cadherin, and phosphorylated Smad2/3. This receptor complex acutely sensitizes nonmalignant breast epithelial cells to activation by typically substimulatory levels of activated TGF-␤. TGF-␤ can promote cellular differentiation or invasion and transformation. As a translational coactivator of TGF-␤, eIF4E confers selective mRNA translation, reprogramming nonmalignant cells to an invasive phenotype by reducing the set point for stimulation by activated TGF-␤. Overexpression of eIF4E may be a proinvasive facilitator of TGF-␤ activity.T ranslation of mRNA involves the recruitment of ribosomes to the capped end of mRNAs by eukaryotic translation initiation factor 4E (eIF4E), RNA helicase eIF4A, and scaffolding protein eIF4G, which comprise the complex known as eIF4F (1). Increased levels of eIF4E have been shown to selectively stimulate the translation of a subset of mRNAs referred to as being more eIF4E sensitive (2), which includes cyclin D1 (proliferation), cMyc (transformation), and Bcl-x L and survivin (survival), among others (3, 4). The nature of the increased requirement for eIF4E in mRNA translation is complex. While certain mRNAs with long or structured 5= untranslated regions (UTRs) possess a greater requirement for eIF4E (5-7), others do not, implicating a combination of 5= UTR structural and sequence motifs in determining the extent to which eIF4E levels control the translation of certain mRNAs (5, 7-10). In part, the increased requirement for eIF4E of more structured 5= UTR mRNAs can be attributed to the need to recruit greater eIF4A RNA helicase activity, which is controlled by eIF4E (11). The availability of translationally active eIF4E is opposed by the eIF4E binding proteins (4E-BPs), which block the eIF4E interaction with eIF4G (1, 12, 13). The 4E-BPs are activated by the loss of kinase mTORC1 phosphorylation during cell stress, such as hypoxia or nutrient deprivation (1).Considerable research from tissue culture (14), animal tumor models (15-17), and a variety of human cancers (18-23) supports the suggestion that overexpression of eIF4E results in prooncogenic activity. eIF4E overexpression and decreased 4E-BP levels or activity are strongly associated with worse clinical outcomes and decreased survival in many human cancers (2,24,25). In breast an...

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“…3 and 4). The TGFβ family has been shown to act as both a tumor suppressor and a tumor promoter (9), depending on context. In many early-stage tumors, TGFβ functions as a tumor suppressor, but in late-stage solid tumors as a tumor promoter (10).…”

Section: Discussionmentioning

confidence: 99%

“…It revealed a number of the upstream regulators involved, thereby shedding light on the tumor dynamics observed. Two ligands from the TGFβ family (8, 9), TGFβ1 (9, 10) and TGFβ2 (11), were found to be centrally involved. The identification of these factors points to age-dependent processes ongoing during tumor progression that can be differentially modulated by proton irradiation.…”

Section: Introductionmentioning

confidence: 99%

Proton Irradiation Augments the Suppression of Tumor Progression Observed with Advanced Age

et al. 2014

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Proton radiation is touted for improved tumor targeting, over standard gamma radiation, due to the physical advantages of ion beams for radiotherapy. Recent studies from our laboratory demonstrate that in addition to these targeting advantages, proton irradiation can inhibit angiogenic and immune factors critical to “hallmark” processes that impact cancer progression, thereby modulating tumor development. Outside the therapeutic utilization of protons, high-energy protons constitute a principal component of galactic cosmic rays and thus are a consideration in carcinogenesis risk for space flight. Given that proton irradiation modulates fundamental biological processes known to decrease with aging (e.g. angiogenesis and immunogenicity), we investigated how proton irradiation impacts tumor advancement as a function of host age, a question with both therapeutic and carcinogenesis implications. Tumor lag time and growth dynamics were tracked, after injection of murine Lewis lung carcinoma (LLC) cells into syngeneic adolescent (68 day) vs. old (736 day) C57BL/6 mice with or without coincident irradiation. Tumor growth was suppressed in old compared to adolescent mice. These differences were further modulated by proton irradiation (1 GeV), with increased inhibition and a significant radiation-altered molecular fingerprint evident in tumors grown in old mice. Through global transcriptome analysis, TGFβ1 and TGFβ2 were determined to be key players that contributed to the tumor dynamics observed. These findings suggest that old hosts exhibit a reduced capacity to support tumor advancement, which can be further reduced by proton irradiation.

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Consequences of Epithelial or Stromal TGFβ1 Depletion in the Mammary Gland

Cited by 11 publications

References 65 publications

Host Age Is a Systemic Regulator of Gene Expression Impacting Cancer Progression

Host Age Is a Systemic Regulator of Gene Expression Impacting Cancer Progression

Eukaryotic Translation Initiation Factor 4E Is a Feed-Forward Translational Coactivator of Transforming Growth Factor β Early Protransforming Events in Breast Epithelial Cells

Proton Irradiation Augments the Suppression of Tumor Progression Observed with Advanced Age

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