CELL CYCLE 2016, VOL. 15, NO. 15, 1975–1976 http://dx.doi.org/10.1080/15384101.2016.1170262
PERSPECTIVE
Mammary gland and radiation: Knowns and unknowns Lidia Luzhna and Olga Kovalchuk Department of Biological Sciences, University of Lethbridge, Lethbridge, AB, Canada
ABSTRACT
ARTICLE HISTORY
Effective breast cancer management and decreasing breast cancer fatalities is contingent upon reliable diagnostic procedures and treatment modalities, including those based on ionizing radiation. On the one hand, ionizing radiation is widely used for cancer diagnostics and therapy, on the other hand it is genotoxic cancer-causing agent. Here we discuss recent studies on the effects of low (diagnostic) and high (treatment) doses of ionizing radiation on healthy breast cells, breast cancer cells, and cancer cells resistant to common drug therapies.
Received 4 December 2015 Revised 5 March 2016 Accepted 20 March 2016
It is generally accepted that the initiation of breast cancer is a result of uncontrolled cellular proliferation and aberrant apoptosis (programmed cell death) due to genetic or epigenetic alterations that involve the activation of proto-oncogenes and the inactivation of tumor suppressor genes.1-4 The successful approach to decreasing breast cancer fatalities depends on reliable diagnostic screening and optimal treatment modalities. Ionizing radiation is widely used for both screening and therapeutic procedures. The effects of radiation exposure are usually limited to the source of radiation, its type, the dose received, the duration of exposure (time), and the radiation sensitivity of body organs. As the use of medical radiation increases, so does public concern regarding potential health risks, and many studies address the issues and controversies of low-dose radiation.5 Any radiation above a certain background level is believed to increase DNA damage and cancer risks in the linear, proportional to the radiation dose mode. The Linear-No-Threshold (LNT) model states there is no dose level below which radiation exposure is safe, and there is a finite probability that even the lowest possible dose may be responsible for cancer initiation.6 Oftentimes cells and organisms exhibit increased sensitivity to low doses of radiation – a low dose hypersensitivity phenomenon, that may be associated with the induced radiation resistance.7-9 The LNT model is regularly challenged by hormesis or the hormetic effect theory, according to which the exposure of cells to low doses of radiation may make them less susceptible to later high-dose exposure and may have health benefits.6,10,11 If the hermetic theory is indeed correct, then the conventional LNT model may create an unnecessary concern and the unjustified avoidance of diagnostic and screening procedures. As such, the current understanding of the effects of low-dose radiation is unclear and is divided between overprotective (LNT) and under-protective (hormesis) views. For instance, the potential increase of a child’s lifetime risk of malignancy from CT scans was reported to be known by CONTACT Olga Kovalchuk © 2016 Taylor & Francis
[email protected]
KEYWORDS
breast cancer; epigenetics; gene expression; ionizing radiation; mammary gland; microRNA
many pediatric physicians.12 Significant dose-response relationships were found with breast cancer risk in patients with tuberculosis who received fluoroscopy frequently.13-14 On the other hand, there is experimental evidence that low-level exposure to ionizing radiation modulates anti-tumor activity by stimulating immune mechanisms mediated by natural killer (NK) cells.15 In this context, animal model-based studies could provide pivotal mechanistic insight into the effects of low-dose radiation on the mammary gland. Our group analyzed and compared the effect of low (diagnostic) and high (treatment) doses of ionizing radiation on healthy breast cells, breast cancer cells, and cancer cells resistant to common drug therapies.16-18 In our recent study, the immediate (96 hours) and prolonged (24 weeks) radiationinduced changes in the mammary gland gene expression were investigated and compared between different radiation doses and energy levels.17 Our results show that ionizing radiation initiates immune and apoptotic responses in normal cells and causes epigenetic alterations that may lead to genomic instability. Radiation exposure leads to early (96 hours) changes in the gene expression. The most profound effect has been shown for the 80 kVp/0.1 Gy dose exposure. Most genetic changes have shown an immunological pathway response to radiation. However, certain oncogenes were activated 24 weeks after the highest dose of radiation. A low dose of radiation has led to the activation of the following pathways: the NK-mediated cytotoxicity pathway, the antigen processing and presentation pathways, chemokine signaling, and the T- and B-cell receptor signaling pathways in the mammary gland. These results demonstrate a possible immune cell infiltration into the irradiated mammary tissue. Overall, the activation of immune response pathways upon radiation exposure may indicate anti-tumor protection and the eradication of damaged cells. Similar effects of internal low-dose irradiation on the gene expression and the activation of the immune response in normal tissues in mice were reported previously.19
University of Lethbridge, 4401 University Drive, Lethbridge, AB, T1K3M4, Canada.
1976
L. LUZHNA AND O. KOVALCHUK
The miRNA profile has been profoundly changed after the lowest (30 kVp/0.1 Gy) and highest (80 kVp/2.5 Gy) doses of X-ray. The increased expression of miR-34a may be linked to cell cycle arrest and apoptosis. The up-regulation of miR-34a was correlated with the down-regulation of its target E2F3 and the upregulation of p53. This data suggests that ionizing radiation at specific high and low doses leads to cell cycle arrest and the possible initiation of apoptosis. The ectopic expressions of miR-34 genes are known to cause a G1 phase arrest.20 Furthermore, the high expression of miR-34a has been shown to induce apoptosis.21 Interestingly, several reports have shown that the miR-34 family is a direct target of p53, and its activation induces apoptosis and cell cycle arrest.22 In addition, the activation of miR34-a by p53 feeds back to p53, and such positive feedback leads to the further activation of p53.23 Moreover, radiation exposure has also led to the translation of the LINE-1 element, whereby the 148-kDa LINE-1 protein level was increased 96 hours after treatment with a low dose and low energy level radiation and remained elevated for 24 weeks after treatment. The mobilization of LINE-1 in the irradiated tissue may potentially contribute to genomic instability.16 In the future, the role of the genes that change their expressions upon exposure to ionizing radiation in the mammary gland tissue should be investigated further. Specifically, the targeted up- or downregulation of these genes in cell culture would allow us to understand well the role of these genes in promoting or preventing carcinogenesis. Identifying the molecular mechanisms of changes in gene expressions and defining which molecular process (e.g., mutation, epigenetic alteration, or transcription factors) within the gene or the gene promoter is affected by ionizing radiation are important. Furthermore, the effects of low dose radiation on breast cancer susceptibility and induction need to be analyzed in detail, with special emphasis on potential low-dose hypersensitivity effects.
Disclosure of potential conflicts of interest No potential conflicts of interest were disclosed.
References [1] Black DM. The genetics of breast cancer. Eur J Cancer 1994; 30A:1957-1961; PMID:7734207; http://dx.doi.org/10.1016/09598049(94)00386-J [2] Russo J, Hu YF, Yang X, Russo IH. Developmental, cellular, and molecular basis of human breast cancer. J Natl Cancer Inst Monogr 2000; 17-37; PMID:10963618; http://dx.doi.org/10.1093/oxfordjournals. jncimonographs.a024241 [3] Hitchins MP. Inheritance of epigenetic aberrations (constitutional epimutations) in cancer susceptibility. Adv Genet 2010; 70:201-243; PMID:20920750; http://dx.doi.org/10.1016/B978-0-12-380866-0.60008-3 [4] Wong EM, Southey MC, Fox SB, Brown MA, Dowty JG, Jenkins MA, Giles GG, Hopper JL, Dobrovic A. Constitutional methylation of the BRCA1 promoter is specifically associated with BRCA1 mutationassociated pathology in early-onset breast cancer. Cancer Prev Res (Phila) 2011; 4:23-33; PMID:20978112; http://dx.doi.org/10.1158/ 1940-6207.CAPR-10-0212 [5] Morgan WF, Bair WJ. Issues in low dose radiation biology: the controversy continues. A perspective. Radiat Res 2013; 179:501-510; PMID:23560636; http://dx.doi.org/10.1667/RR3306.1
[6] Mullenders L, Atkinson M, Paretzke H, Sabatier L, Bouffler S. Assessing cancer risks of low-dose radiation. Nat Rev Cancer 2009; 9:596604; PMID:19629073; http://dx.doi.org/10.1038/nrc2677 [7] Chandna S, Dwarakanath BS, Khaitan D, Mathew TL, Jain V. Low-dose radiation hypersensitivity in human tumor cell lines: effects of cell-cell contact and nutritional deprivation. Radiat Res 2002; 157:516-525; PMID:11966317; http://dx.doi.org/10.1667/00337587(2002)157%5b0516:LDRHIH%5d2.0.CO;2 [8] Cherubini R, De Nadal V, Gerardi S. Hyper-radiosensitivity and induced radioresistance and bystander effects in rodent and human cells as a function of radiation quality. Radiat Prot Dosimetry 2015; 166:137-141; PMID:25953796; http://dx.doi.org/10.1093/rpd/ncv294 [9] Das S, Singh R, George D, Vijaykumar TS, John S. Radiobiological response of cervical cancer cell line in low dose region: Evidence of Low Dose Hypersensitivity (HRS) and Induced Radioresistance (IRR). J Clin Diagn Res 2015; 9:XC05-XC08; PMID:26266200 [10] Calabrese EJ, Baldwin LA. Hormesis: the dose-response revolution. Ann Rev Pharmacol Toxicol 2003; 43:175-197; PMID:12195028; http://dx.doi.org/10.1146/annurev.pharmtox.43.100901.140223 [11] Feinendegen LE. Evidence for beneficial low level radiation effects and radiation hormesis. Br J Radiol 2005; 78:3-7; PMID:15673519; http://dx.doi.org/10.1259/bjr/63353075 [12] Boutis K, Fischer J, Freedman SB, Thomas KE. Radiation exposure from imaging tests in pediatric emergency medicine: a survey of physician knowledge and risk disclosure practices. J Emer Med 2014; 47:3644; PMID:24698509; http://dx.doi.org/10.1016/j.jemermed.2014.01.030 [13] Boice JD, Jr., Preston D, Davis FG, Monson RR. Frequent chest X-ray fluoroscopy and breast cancer incidence among tuberculosis patients in Massachusetts. Radiat Res 1991; 125:214-222; PMID:1996380; http://dx.doi.org/10.2307/3577890 [14] Howe GR, McLaughlin J. Breast cancer mortality between 1950 and 1987 after exposure to fractionated moderate-dose-rate ionizing radiation in the Canadian fluoroscopy cohort study and a comparison with breast cancer mortality in the atomic bomb survivors study. Radiat Res 1996; 145:694-707; PMID:8643829; http://dx.doi.org/10.2307/3579360 [15] Nowosielska EM, Wrembel-Wargocka J, Cheda A, Lisiak E, Janiak MK. Low-level exposures to ionising radiation modulate the antitumour activity of murine NK cells. Nukleonika 2005; 50:S21-S24. [16] Luzhna L, Ilnytskyy Y, Kovalchuk O. Mobilization of LINE-1 in irradiated mammary gland tissue may potentially contribute to low dose radiation-induced genomic instability. Gen Cancer 2015; 6:71-81; PMID:25821563 [17] Luzhna L, Kovalchuk O. Low dose irradiation profoundly affects transcriptome and microRNAme in rat mammary gland tissues. Oncoscience 2014; 1:751-762; PMID:25594002 [18] Luzhna L, Lykkesfeldt AE, Kovalchuk O. Altered radiation responses of breast cancer cells resistant to hormonal therapy. Oncotarget 2015; 6:1678-1694; PMID:25682200; http://dx.doi.org/10.18632/ oncotarget.3188 [19] Schuler E, Parris TZ, Rudqvist N, Helou K, Forssell-Aronsson E. Effects of internal low-dose irradiation from 131I on gene expression in normal tissues in Balb/c mice. EJNMMI Res 2011; 1:29; PMID:22214497; http://dx.doi.org/10.1186/2191-219X-1-29 [20] Tarasov V, Jung P, Verdoodt B, Lodygin D, Epanchintsev A, Menssen A, Meister G, Hermeking H. Differential regulation of microRNAs by p53 revealed by massively parallel sequencing: miR34a is a p53 target that induces apoptosis and G1-arrest. Cell Cycle 2007; 6:1586-1593; PMID:17554199; http://dx.doi.org/10.4161/cc.6. 13.4436 [21] Raver-Shapira N, Marciano E, Meiri E, Spector Y, Rosenfeld N, Moskovits N, Bentwich Z, Oren M. Transcriptional activation of miR34a contributes to p53-mediated apoptosis. Mol Cell 2007; 26:731-743; PMID:17540598; http://dx.doi.org/10.1016/j.molcel.2007.05.017 [22] Bommer GT, Gerin I, Feng Y, Kaczorowski AJ, Kuick R, Love RE, Zhai Y, Giordano TJ, Qin ZS, Moore BB, et al. p53-mediated activation of miRNA34 candidate tumor-suppressor genes. Curr Biols 2007; 17:12981307; PMID:17656095; http://dx.doi.org/10.1016/j.cub.2007.06.068 [23] Hermeking H. The miR-34 family in cancer and apoptosis. Cell Death Different 2010; 17:193-199; PMID:19461653; http://dx.doi. org/10.1038/cdd.2009.56
PERSPECTIVE
Mammary gland and radiation: Knowns and unknowns Lidia Luzhna and Olga Kovalchuk Department of Biological Sciences, University of Lethbridge, Lethbridge, AB, Canada
ABSTRACT
ARTICLE HISTORY
Effective breast cancer management and decreasing breast cancer fatalities is contingent upon reliable diagnostic procedures and treatment modalities, including those based on ionizing radiation. On the one hand, ionizing radiation is widely used for cancer diagnostics and therapy, on the other hand it is genotoxic cancer-causing agent. Here we discuss recent studies on the effects of low (diagnostic) and high (treatment) doses of ionizing radiation on healthy breast cells, breast cancer cells, and cancer cells resistant to common drug therapies.
Received 4 December 2015 Revised 5 March 2016 Accepted 20 March 2016
It is generally accepted that the initiation of breast cancer is a result of uncontrolled cellular proliferation and aberrant apoptosis (programmed cell death) due to genetic or epigenetic alterations that involve the activation of proto-oncogenes and the inactivation of tumor suppressor genes.1-4 The successful approach to decreasing breast cancer fatalities depends on reliable diagnostic screening and optimal treatment modalities. Ionizing radiation is widely used for both screening and therapeutic procedures. The effects of radiation exposure are usually limited to the source of radiation, its type, the dose received, the duration of exposure (time), and the radiation sensitivity of body organs. As the use of medical radiation increases, so does public concern regarding potential health risks, and many studies address the issues and controversies of low-dose radiation.5 Any radiation above a certain background level is believed to increase DNA damage and cancer risks in the linear, proportional to the radiation dose mode. The Linear-No-Threshold (LNT) model states there is no dose level below which radiation exposure is safe, and there is a finite probability that even the lowest possible dose may be responsible for cancer initiation.6 Oftentimes cells and organisms exhibit increased sensitivity to low doses of radiation – a low dose hypersensitivity phenomenon, that may be associated with the induced radiation resistance.7-9 The LNT model is regularly challenged by hormesis or the hormetic effect theory, according to which the exposure of cells to low doses of radiation may make them less susceptible to later high-dose exposure and may have health benefits.6,10,11 If the hermetic theory is indeed correct, then the conventional LNT model may create an unnecessary concern and the unjustified avoidance of diagnostic and screening procedures. As such, the current understanding of the effects of low-dose radiation is unclear and is divided between overprotective (LNT) and under-protective (hormesis) views. For instance, the potential increase of a child’s lifetime risk of malignancy from CT scans was reported to be known by CONTACT Olga Kovalchuk © 2016 Taylor & Francis
[email protected]
KEYWORDS
breast cancer; epigenetics; gene expression; ionizing radiation; mammary gland; microRNA
many pediatric physicians.12 Significant dose-response relationships were found with breast cancer risk in patients with tuberculosis who received fluoroscopy frequently.13-14 On the other hand, there is experimental evidence that low-level exposure to ionizing radiation modulates anti-tumor activity by stimulating immune mechanisms mediated by natural killer (NK) cells.15 In this context, animal model-based studies could provide pivotal mechanistic insight into the effects of low-dose radiation on the mammary gland. Our group analyzed and compared the effect of low (diagnostic) and high (treatment) doses of ionizing radiation on healthy breast cells, breast cancer cells, and cancer cells resistant to common drug therapies.16-18 In our recent study, the immediate (96 hours) and prolonged (24 weeks) radiationinduced changes in the mammary gland gene expression were investigated and compared between different radiation doses and energy levels.17 Our results show that ionizing radiation initiates immune and apoptotic responses in normal cells and causes epigenetic alterations that may lead to genomic instability. Radiation exposure leads to early (96 hours) changes in the gene expression. The most profound effect has been shown for the 80 kVp/0.1 Gy dose exposure. Most genetic changes have shown an immunological pathway response to radiation. However, certain oncogenes were activated 24 weeks after the highest dose of radiation. A low dose of radiation has led to the activation of the following pathways: the NK-mediated cytotoxicity pathway, the antigen processing and presentation pathways, chemokine signaling, and the T- and B-cell receptor signaling pathways in the mammary gland. These results demonstrate a possible immune cell infiltration into the irradiated mammary tissue. Overall, the activation of immune response pathways upon radiation exposure may indicate anti-tumor protection and the eradication of damaged cells. Similar effects of internal low-dose irradiation on the gene expression and the activation of the immune response in normal tissues in mice were reported previously.19
University of Lethbridge, 4401 University Drive, Lethbridge, AB, T1K3M4, Canada.
1976
L. LUZHNA AND O. KOVALCHUK
The miRNA profile has been profoundly changed after the lowest (30 kVp/0.1 Gy) and highest (80 kVp/2.5 Gy) doses of X-ray. The increased expression of miR-34a may be linked to cell cycle arrest and apoptosis. The up-regulation of miR-34a was correlated with the down-regulation of its target E2F3 and the upregulation of p53. This data suggests that ionizing radiation at specific high and low doses leads to cell cycle arrest and the possible initiation of apoptosis. The ectopic expressions of miR-34 genes are known to cause a G1 phase arrest.20 Furthermore, the high expression of miR-34a has been shown to induce apoptosis.21 Interestingly, several reports have shown that the miR-34 family is a direct target of p53, and its activation induces apoptosis and cell cycle arrest.22 In addition, the activation of miR34-a by p53 feeds back to p53, and such positive feedback leads to the further activation of p53.23 Moreover, radiation exposure has also led to the translation of the LINE-1 element, whereby the 148-kDa LINE-1 protein level was increased 96 hours after treatment with a low dose and low energy level radiation and remained elevated for 24 weeks after treatment. The mobilization of LINE-1 in the irradiated tissue may potentially contribute to genomic instability.16 In the future, the role of the genes that change their expressions upon exposure to ionizing radiation in the mammary gland tissue should be investigated further. Specifically, the targeted up- or downregulation of these genes in cell culture would allow us to understand well the role of these genes in promoting or preventing carcinogenesis. Identifying the molecular mechanisms of changes in gene expressions and defining which molecular process (e.g., mutation, epigenetic alteration, or transcription factors) within the gene or the gene promoter is affected by ionizing radiation are important. Furthermore, the effects of low dose radiation on breast cancer susceptibility and induction need to be analyzed in detail, with special emphasis on potential low-dose hypersensitivity effects.
Disclosure of potential conflicts of interest No potential conflicts of interest were disclosed.
References [1] Black DM. The genetics of breast cancer. Eur J Cancer 1994; 30A:1957-1961; PMID:7734207; http://dx.doi.org/10.1016/09598049(94)00386-J [2] Russo J, Hu YF, Yang X, Russo IH. Developmental, cellular, and molecular basis of human breast cancer. J Natl Cancer Inst Monogr 2000; 17-37; PMID:10963618; http://dx.doi.org/10.1093/oxfordjournals. jncimonographs.a024241 [3] Hitchins MP. Inheritance of epigenetic aberrations (constitutional epimutations) in cancer susceptibility. Adv Genet 2010; 70:201-243; PMID:20920750; http://dx.doi.org/10.1016/B978-0-12-380866-0.60008-3 [4] Wong EM, Southey MC, Fox SB, Brown MA, Dowty JG, Jenkins MA, Giles GG, Hopper JL, Dobrovic A. Constitutional methylation of the BRCA1 promoter is specifically associated with BRCA1 mutationassociated pathology in early-onset breast cancer. Cancer Prev Res (Phila) 2011; 4:23-33; PMID:20978112; http://dx.doi.org/10.1158/ 1940-6207.CAPR-10-0212 [5] Morgan WF, Bair WJ. Issues in low dose radiation biology: the controversy continues. A perspective. Radiat Res 2013; 179:501-510; PMID:23560636; http://dx.doi.org/10.1667/RR3306.1
[6] Mullenders L, Atkinson M, Paretzke H, Sabatier L, Bouffler S. Assessing cancer risks of low-dose radiation. Nat Rev Cancer 2009; 9:596604; PMID:19629073; http://dx.doi.org/10.1038/nrc2677 [7] Chandna S, Dwarakanath BS, Khaitan D, Mathew TL, Jain V. Low-dose radiation hypersensitivity in human tumor cell lines: effects of cell-cell contact and nutritional deprivation. Radiat Res 2002; 157:516-525; PMID:11966317; http://dx.doi.org/10.1667/00337587(2002)157%5b0516:LDRHIH%5d2.0.CO;2 [8] Cherubini R, De Nadal V, Gerardi S. Hyper-radiosensitivity and induced radioresistance and bystander effects in rodent and human cells as a function of radiation quality. Radiat Prot Dosimetry 2015; 166:137-141; PMID:25953796; http://dx.doi.org/10.1093/rpd/ncv294 [9] Das S, Singh R, George D, Vijaykumar TS, John S. Radiobiological response of cervical cancer cell line in low dose region: Evidence of Low Dose Hypersensitivity (HRS) and Induced Radioresistance (IRR). J Clin Diagn Res 2015; 9:XC05-XC08; PMID:26266200 [10] Calabrese EJ, Baldwin LA. Hormesis: the dose-response revolution. Ann Rev Pharmacol Toxicol 2003; 43:175-197; PMID:12195028; http://dx.doi.org/10.1146/annurev.pharmtox.43.100901.140223 [11] Feinendegen LE. Evidence for beneficial low level radiation effects and radiation hormesis. Br J Radiol 2005; 78:3-7; PMID:15673519; http://dx.doi.org/10.1259/bjr/63353075 [12] Boutis K, Fischer J, Freedman SB, Thomas KE. Radiation exposure from imaging tests in pediatric emergency medicine: a survey of physician knowledge and risk disclosure practices. J Emer Med 2014; 47:3644; PMID:24698509; http://dx.doi.org/10.1016/j.jemermed.2014.01.030 [13] Boice JD, Jr., Preston D, Davis FG, Monson RR. Frequent chest X-ray fluoroscopy and breast cancer incidence among tuberculosis patients in Massachusetts. Radiat Res 1991; 125:214-222; PMID:1996380; http://dx.doi.org/10.2307/3577890 [14] Howe GR, McLaughlin J. Breast cancer mortality between 1950 and 1987 after exposure to fractionated moderate-dose-rate ionizing radiation in the Canadian fluoroscopy cohort study and a comparison with breast cancer mortality in the atomic bomb survivors study. Radiat Res 1996; 145:694-707; PMID:8643829; http://dx.doi.org/10.2307/3579360 [15] Nowosielska EM, Wrembel-Wargocka J, Cheda A, Lisiak E, Janiak MK. Low-level exposures to ionising radiation modulate the antitumour activity of murine NK cells. Nukleonika 2005; 50:S21-S24. [16] Luzhna L, Ilnytskyy Y, Kovalchuk O. Mobilization of LINE-1 in irradiated mammary gland tissue may potentially contribute to low dose radiation-induced genomic instability. Gen Cancer 2015; 6:71-81; PMID:25821563 [17] Luzhna L, Kovalchuk O. Low dose irradiation profoundly affects transcriptome and microRNAme in rat mammary gland tissues. Oncoscience 2014; 1:751-762; PMID:25594002 [18] Luzhna L, Lykkesfeldt AE, Kovalchuk O. Altered radiation responses of breast cancer cells resistant to hormonal therapy. Oncotarget 2015; 6:1678-1694; PMID:25682200; http://dx.doi.org/10.18632/ oncotarget.3188 [19] Schuler E, Parris TZ, Rudqvist N, Helou K, Forssell-Aronsson E. Effects of internal low-dose irradiation from 131I on gene expression in normal tissues in Balb/c mice. EJNMMI Res 2011; 1:29; PMID:22214497; http://dx.doi.org/10.1186/2191-219X-1-29 [20] Tarasov V, Jung P, Verdoodt B, Lodygin D, Epanchintsev A, Menssen A, Meister G, Hermeking H. Differential regulation of microRNAs by p53 revealed by massively parallel sequencing: miR34a is a p53 target that induces apoptosis and G1-arrest. Cell Cycle 2007; 6:1586-1593; PMID:17554199; http://dx.doi.org/10.4161/cc.6. 13.4436 [21] Raver-Shapira N, Marciano E, Meiri E, Spector Y, Rosenfeld N, Moskovits N, Bentwich Z, Oren M. Transcriptional activation of miR34a contributes to p53-mediated apoptosis. Mol Cell 2007; 26:731-743; PMID:17540598; http://dx.doi.org/10.1016/j.molcel.2007.05.017 [22] Bommer GT, Gerin I, Feng Y, Kaczorowski AJ, Kuick R, Love RE, Zhai Y, Giordano TJ, Qin ZS, Moore BB, et al. p53-mediated activation of miRNA34 candidate tumor-suppressor genes. Curr Biols 2007; 17:12981307; PMID:17656095; http://dx.doi.org/10.1016/j.cub.2007.06.068 [23] Hermeking H. The miR-34 family in cancer and apoptosis. Cell Death Different 2010; 17:193-199; PMID:19461653; http://dx.doi. org/10.1038/cdd.2009.56
