TGFβ: Roles in DNA Damage Responses

Andarawewa, Kumari L.; Kirshner, Julia; Mott, Joni D.; Barcellos‐Hoff, Mary Helen

doi:10.1007/978-1-59745-293-9_21

Cited by 5 publications

(4 citation statements)

References 86 publications

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“…Network analysis of the IHC-156 revealed TGFβ hubs and enrichment of TGFβ mediated genes. Our earlier functional studies showed that radiation-induced TGFβ activation in vivo mediates extracellular matrix remodeling, cell fate decisions, ATM kinase control of the DNA damage response, and EMT (reviewed in (Andarawewa et al, 2007)). Expression analysis of irradiated Tgfb1 heterozygote and wild type mammary gland further underscored the considerable influence of TGFβ in the tissue response to radiation and motivated the radiation chimera experiment using Tgfb1 heterozygote hosts.…”

Section: Discussionmentioning

confidence: 99%

Radiation Acts on the Microenvironment to Affect Breast Carcinogenesis by Distinct Mechanisms that Decrease Cancer Latency and Affect Tumor Type

et al. 2011

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SUMMARY Tissue microenvironment is an important determinant of carcinogenesis. We demonstrate that ionizing radiation, a known carcinogen, affects cancer frequency and characteristics by acting on the microenvironment. Using a mammary chimera model in which an irradiated host is transplanted with oncogenic Trp53 null epithelium, we show accelerated development of aggressive tumors whose molecular signatures were distinct from non-irradiated hosts. Molecular and genetic approaches show that TGFβ mediated tumor acceleration; molecular signatures implicated TGFβ and genetically reducing TGFβ abrogated the effect on latency. Surprisingly, tumors from irradiated hosts were predominantly estrogen receptor negative. This effect was TGFβ independent and linked to mammary stem cell activity. Thus the irradiated microenvironment affects latency and clinically relevant features of cancer through distinct and unexpected mechanisms.

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Section: Discussionmentioning

confidence: 99%

Radiation Acts on the Microenvironment to Affect Breast Carcinogenesis by Distinct Mechanisms that Decrease Cancer Latency and Affect Tumor Type

et al. 2011

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“…Recent data suggest an even more proximal role for TGFβ in radiotherapy (reviewed in [ 64 ]). Breast cancer radiotherapy targets the tumor with the goal of inducing DNA damage resulting in cancer cell death, which increases long term patient survival [ 65 ].…”

Section: Tgfβ a Malicious Bystander During Cancer Therapymentioning

confidence: 99%

Transforming growth factor-β in breast cancer: too much, too late

2009

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The contribution of transforming growth factor (TGF)β to breast cancer has been studied from a myriad perspectives since seminal studies more than two decades ago. Although the action of TGFβ as a canonical tumor suppressor in breast is without a doubt, there is compelling evidence that TGFβ is frequently subverted in a malignant plexus that drives breast cancer. New knowledge that TGFβ regulates the DNA damage response, which underlies cancer therapy, reveals another facet of TGFβ biology that impedes cancer control. Too much TGFβ, too late in cancer progression is the fundamental motivation for pharmaceutical inhibition. Transforming growth factor-β β in breast cancer progressionThe breadth and scope of research to define the complex roles that transforming growth factor (TGF)β plays during mammary development and breast cancer now exceeds a thousand papers. Even by the time the elegant and oftquoted study by Silberstein and Daniel in 1987 [1] put TGFβ on the mammary map as an important regulator of breast development, there was clear evidence that cancer could subvert this powerful growth inhibitory signal [2].In the past decade or so, animal tumor studies that target over-expression or inactivation of various TGFβ signaling components to different epithelial compartments have resulted in a bewildering array of conclusions due to the pleiotropic and highly context-dependent action of TGFβ on cancer suppression or progression. It is now generally agreed that during early tumor outgrowth, elevated TGFβ is tumor suppressive, whereas at later stages there is a switch towards malignant conversion and progression [3,4], as shown in neu-induced mammary tumors [5]. Inactivation of tumor suppressor genes, the sequential acquisition of oncogenic mutations, and epigenetic changes within the cancer genome divert the canonical growth inhibitory arm of the TGFβ signaling pathway towards behaviors that increase motility, invasion and metastasis (reviewed in [4]). Consistent with the response to TGFβ evolving from growth inhibition to tumor progression during advanced malignancy, the majority of breast tumors, including their metastases, are positive for nuclear phosphorylated Smad2, indicating an actively signaling TGFβ pathway [6,7].Loss of TGFβ growth inhibition and increased expression of TGFβ have been associated with malignant conversion and progression in breast, as well as gastric, endometrial, ovarian, and cervical cancers, glioma and melanoma (reviewed in [4,8]). But specific mutation of TGFβ signaling components occurs only occasionally in breast cancers. Rather, TGFβ growth response is abrogated by changes in the profile of other active signaling networks or the relative availability of transcriptional co-repressors or co-activators that bind to and modulate the canonical Smad pathway. Estrogens also appear to negatively regulate TGFβ signaling in breast cancer [9] and there is evidence that many pathway components may be epigenetically regulated during critical transitions in malignant progression [10]....

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“…There is substantial evidence that TGFβ plays a crucial role in the response to ionizing radiation (2). TGFβ is a pleio-tropic cytokine that is important in normal tissue homeo-stasis, regulates inflammation and immune responses, and suppresses epithelial proliferation.…”

Section: Introductionmentioning

confidence: 99%

“…A new role for TGFβ in mediating the rapid execution of the DNA damage response (DDR) has been identified (reviewed in ref 2). Perhaps the first indication of its critical role was the observation that epithelial tissues of Tgfb1 heterozygote embryos exposed in utero to 5 Gy showed significantly less radiation-induced apoptosis and Tgfb1 null embryos fail to undergo either apoptosis or inhibition of cell cycle (17).…”

Section: Introductionmentioning

confidence: 99%

TGFβ1 Inhibition Increases the Radiosensitivity of Breast Cancer CellsIn Vitroand Promotes Tumor Control by RadiationIn Vivo

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Pal

Pilones

et al. 2011

Clinical Cancer Research

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Purpose To determine whether inhibition of TGFβ signaling prior to irradiation sensitizes human and murine cancer cells in vitro and in vivo. Experimental Design TGFβ-mediated growth and Smad phosphorylation of MCF7, Hs578T, MDA-MB-231, and T47D human breast cancer cell lines were examined and correlated with clonogenic survival following graded radiation doses with and without pretreatment with LY364947, a small molecule inhibitor of the TGFβ type I receptor kinase. The DNA damage response was assessed in irradiated MDA-MB-231 cells pretreated with LY364947 in vitro and LY2109761, a pharmacokinetically stable inhibitor of TGFβ signaling, in vivo. The in vitro response of a syngeneic murine tumor, 4T1, was tested using a TGFβ neutralizing antibody, 1D11, with single or fractionated radiation doses in vivo. Results Human breast cancer cell lines pretreated with TGFβ small molecule inhibitor were radio-sensitized, irrespective of sensitivity to TGFβ growth inhibition. Consistent with increased clonogenic cell death, radiation-induced phosphorylation of H2AX and p53 was significantly reduced in MDA-MB-231 triple-negative breast cancer cells when pretreated in vitro or in vivo with a TGFfS type I receptor kinase inhibitor. Moreover, TGFβ neutralizing antibodies increased radiation sensitivity, blocked γH2AX foci formation, and significantly increased tumor growth delay in 4T1 murine mammary tumors in response to single and fractionated radiation exposures. Conclusion These results show that TGFβ inhibition prior to radiation attenuated DNA damage responses, increased clonogenic cell death, and promoted tumor growth delay, and thus may be an effective adjunct in cancer radiotherapy.

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TGFβ: Roles in DNA Damage Responses

Cited by 5 publications

References 86 publications

Radiation Acts on the Microenvironment to Affect Breast Carcinogenesis by Distinct Mechanisms that Decrease Cancer Latency and Affect Tumor Type

Radiation Acts on the Microenvironment to Affect Breast Carcinogenesis by Distinct Mechanisms that Decrease Cancer Latency and Affect Tumor Type

Transforming growth factor-β in breast cancer: too much, too late

TGFβ1 Inhibition Increases the Radiosensitivity of Breast Cancer CellsIn Vitroand Promotes Tumor Control by RadiationIn Vivo

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