Two Faces of TGF-Beta1 in Breast Cancer

Breast cancer (BC) is potentially life-threatening malignancy that still causes high mortality among women. Scientific research in this field is focused on deeper understanding of pathogenesis and progressing of BC, in order to develop relevant diagnosis and improve therapeutic treatment. Multifunctional cytokine TGF-β1 is one of many factors that have a direct influence on BC pathophysiology. Expression of TGF-β1, induction of canonical and noncanonical signaling pathways, and mutations in genes encoding TGF-β1 and its receptors are correlated with oncogenic activity of this cytokine. In early stages of BC this cytokine inhibits epithelial cell cycle progression and promotes apoptosis, showing tumor suppressive effects. However, in late stages, TGF-β1 is linked with increased tumor progression, higher cell motility, cancer invasiveness, and metastasis. It is also involved in cancer microenvironment modification and promotion of epithelial to mesenchymal transition (EMT). This review summarizes the current knowledge on the phenomenon called “TGF-β1 paradox”, showing that better understanding of TGF-β1 functions can be a step towards development of new therapeutic approaches. According to current knowledge several drugs against TGF-β1 have been developed and are either in nonclinical or in early stages of clinical investigation.

[1]  James W. Smyth,et al.  TGF-β-induced activation of mTOR complex 2 drives epithelial–mesenchymal transition and cell invasion , 2012, Journal of Cell Science.

[2]  J. Balko,et al.  TGF-β inhibition enhances chemotherapy action against triple-negative breast cancer. , 2013, The Journal of clinical investigation.

[3]  Iñaki F Trocóniz,et al.  Semi-mechanistic modelling of the tumour growth inhibitory effects of LY2157299, a new type I receptor TGF-beta kinase antagonist, in mice. , 2008, European journal of cancer.

[4]  C. Arteaga.  Inhibition of TGFβ signaling in cancer therapy , 2006 .

[5]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.

[6]  Samy Lamouille,et al.  Cell size and invasion in TGF-β–induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathway , 2007, The Journal of cell biology.

[7]  A. Wen,et al.  Resveratrol Sensitizes Tamoxifen in Antiestrogen-Resistant Breast Cancer Cells with Epithelial-Mesenchymal Transition Features , 2013, International journal of molecular sciences.

[8]  Ps Patel,et al.  Clinical significance of matrix metalloproteinase 2 and 9 in breast cancer. , 2009, Indian journal of cancer.

[9]  S. Wang,et al.  The Functional Crosstalk between HER2 Tyrosine Kinase and TGF-β Signaling in Breast Cancer Malignancy , 2011, Journal of signal transduction.

[10]  Samy Lamouille,et al.  Regulation of epithelial-mesenchymal and mesenchymal-epithelial transitions by microRNAs. , 2013, Current opinion in cell biology.

[11]  M. Korpal,et al.  Targeting the transforming growth factor-beta signalling pathway in metastatic cancer. , 2010, European journal of cancer.

[12]  H. Moses,et al.  Inhibition of TGF-beta with neutralizing antibodies prevents radiation-induced acceleration of metastatic cancer progression. , 2007, The Journal of clinical investigation.

[13]  Dong-Wan Kim,et al.  Elevated TGF-β1 Secretion and Down-Modulation of NKG2D Underlies Impaired NK Cytotoxicity in Cancer Patients1 , 2004, The Journal of Immunology.

[14]  L. Coussens,et al.  Paradoxical roles of the immune system during cancer development , 2006, Nature Reviews Cancer.

[15]  B. Kos-Kudła,et al.  Transforming growth factor beta1 (TGFbeta1) in physiology and pathology , 2013 .

[16]  D. Hume,et al.  Concordant epigenetic silencing of transforming growth factor-beta signaling pathway genes occurs early in breast carcinogenesis. , 2007, Cancer research.

[17]  Brian Bierie,et al.  Transforming growth factor beta (TGF-beta) and inflammation in cancer. , 2010, Cytokine & growth factor reviews.

[18]  Hiroshi I. Suzuki,et al.  Autophagy is activated by TGF-beta and potentiates TGF-beta-mediated growth inhibition in human hepatocellular carcinoma cells. , 2009, Cancer research.

[19]  J. Massagué,et al.  Genetic determinants of cancer metastasis , 2007, Nature Reviews Genetics.

[20]  R. Clarke,et al.  Reversal of tamoxifen resistance of human breast carcinomas in vivo by neutralizing antibodies to transforming growth factor-beta. , 1999, Journal of the National Cancer Institute.

[21]  Kohei Miyazono,et al.  Autocrine TGF-β protects breast cancer cells from apoptosis through reduction of BH3-only protein, Bim. , 2011, Journal of biochemistry.

[22]  Erik Meulmeester,et al.  The dynamic roles of TGF‐β in cancer , 2011, The Journal of pathology.

[23]  C. Arteaga,et al.  When Tumor Suppressor TGFβ Meets the HER2 (ERBB2) Oncogene , 2011, Journal of Mammary Gland Biology and Neoplasia.

[24]  R. Beroukhim,et al.  Molecular definition of breast tumor heterogeneity. , 2007, Cancer cell.

[25]  M. Reiss,et al.  Targeting Endogenous Transforming Growth Factor β Receptor Signaling in SMAD4-Deficient Human Pancreatic Carcinoma Cells Inhibits Their Invasive Phenotype 1 , 2004, Cancer Research.

[26]  Dong-Wan Kim,et al.  Elevated TGF-b1 Secretion and Downmodulation of NKG2D Underlies Impaired NK Cytotoxicity in Cancer Patients , 2004 .

[27]  M. Barcellos-Hoff,et al.  Activated type I TGFβ receptor kinase enhances the survival of mammary epithelial cells and accelerates tumor progression , 2006, Oncogene.

[28]  Luzhe Sun,et al.  Doxorubicin in Combination with a Small TGFβ Inhibitor: A Potential Novel Therapy for Metastatic Breast Cancer in Mouse Models , 2010, PloS one.

[29]  P. Porter.  Global trends in breast cancer incidence and mortality. , 2009, Salud publica de Mexico.

[30]  G. Alexe,et al.  Transforming growth factor-β signaling: emerging stem cell target in metastatic breast cancer? , 2009, Breast Cancer Research and Treatment.

[31]  江幡 正悟.  Ki26894, a novel transforming growth factor-β type 1 receptor kinase inhibitor, inhibits in vitro invasion and in vivo bone metastasis of a human breast cancer cell line , 2007 .

[32]  Xiu-fen Lei,et al.  Inhibition of pulmonary and skeletal metastasis by a transforming growth factor-beta type I receptor kinase inhibitor. , 2006, Cancer research.

[33]  J. Debnath,et al.  Induction of autophagy during extracellular matrix detachment promotes cell survival. , 2007, Molecular biology of the cell.

[34]  S. Hayward,et al.  Loss of TGF-β type II receptor in fibroblasts promotes mammary carcinoma growth and invasion through upregulation of TGF-α-, MSP- and HGF-mediated signaling networks , 2005, Oncogene.

[35]  R. Weissleder,et al.  Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-β signals in vivo , 2005 .

[36]  M. Duffy,et al.  Matrix metalloproteinase expression and outcome in patients with breast cancer: analysis of a published database. , 2008, Annals of oncology : official journal of the European Society for Medical Oncology.

[37]  Domenico Coppola,et al.  MicroRNA-155 Is Regulated by the Transforming Growth Factor β/Smad Pathway and Contributes to Epithelial Cell Plasticity by Targeting RhoA , 2008, Molecular and Cellular Biology.

[38]  C. Hill,et al.  Alterations in components of the TGF-beta superfamily signaling pathways in human cancer. , 2006, Cytokine & growth factor reviews.

[39]  J. Massagué,et al.  TGFβ in Cancer , 2008, Cell.

[40]  J. Downward,et al.  Ras and TGF[beta] cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. , 2002, The Journal of cell biology.

[41]  Kevin Bray,et al.  Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. , 2006, Cancer cell.

[42]  B. Park,et al.  Duel nature of TGF-β signaling: tumor suppressor vs. tumor promoter , 2005 .

[43]  Jing Zhong,et al.  Transforming growth factor-β signaling in tumor initiation, progression and therapy in breast cancer: an update , 2011, Cell and Tissue Research.

[44]  L. Zerbini,et al.  The oncogenic TBX3 is a downstream target and mediator of the TGF-β1 signaling pathway , 2013, Molecular biology of the cell.

[45]  L. Wakefield,et al.  TGF-β switches from tumor suppressor to prometastatic factor in a model of breast cancer progression , 2003 .

[46]  E. Morselli,et al.  Oncosuppressive functions of autophagy. , 2011, Antioxidants & redox signaling.

[47]  H. Brauch,et al.  A novel functional polymorphism in the transforming growth factor-beta2 gene promoter and tumor progression in breast cancer. , 2006, Cancer research.

[48]  James W. Smyth,et al.  TGF-β-induced activation of mTOR complex 2 drives epithelial–mesenchymal transition and cell invasion , 2012, Development.

[49]  I. Keklikoglou,et al.  MicroRNA-520/373 family functions as a tumor suppressor in estrogen receptor negative breast cancer by targeting NF-κB and TGF-β signaling pathways , 2012, Oncogene.

[50]  L. Fu,et al.  Tumor Secretion of CCL22 Activates Intratumoral Treg Infiltration and Is Independent Prognostic Predictor of Breast Cancer , 2013, PloS one.

[51]  Jeong-Seok Nam,et al.  Targeting the Transforming Growth Factor-β Signaling in Cancer Therapy , 2013, Biomolecules & therapeutics.

[52]  C. Panis,et al.  Screening of circulating TGF-β levels and its clinicopathological significance in human breast cancer. , 2013, Anticancer research.

[53]  Li Yang,et al.  TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression. , 2010, Trends in immunology.

[54]  Samy Lamouille,et al.  TGF-&bgr; signaling and epithelial–mesenchymal transition in cancer progression , 2013, Current opinion in oncology.

[55]  B. Moeller,et al.  The type III TGF-β receptor suppresses breast cancer progression , 2007 .

[56]  Gerhard Christofori,et al.  EMT, the cytoskeleton, and cancer cell invasion , 2009, Cancer and Metastasis Reviews.

[57]  K. Miyazono,et al.  Tumor-promoting functions of transforming growth factor-β in progression of cancer , 2012, Upsala journal of medical sciences.

[58]  D. Carbone,et al.  Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. , 2008, Cancer cell.

[59]  David Padua,et al.  Roles of TGFβ in metastasis , 2009, Cell Research.

[60]  Joshua LaBaer,et al.  Cooperation of the ErbB2 receptor and transforming growth factor beta in induction of migration and invasion in mammary epithelial cells. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[61]  A. Ghanbari,et al.  Tranilast enhances the anti-tumor effects of tamoxifen on human breast cancer cells in vitro , 2013, Journal of Biomedical Science.

[62]  Andrei V Bakin,et al.  TAK1 is required for TGF-β1-mediated regulation of matrix metalloproteinase-9 and metastasis , 2007, Oncogene.

[63]  J. Massagué,et al.  TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. , 2005, Cancer cell.

[64]  M. F. Shannon,et al.  An autocrine TGF-β/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial-mesenchymal transition , 2011, Molecular biology of the cell.

[65]  M. Korc,et al.  Soluble type II transforming growth factor-beta receptor attenuates expression of metastasis-associated genes and suppresses pancreatic cancer cell metastasis. , 2002, Molecular cancer therapeutics.

[66]  A. Jemal,et al.  Cancer statistics, 2012 , 2012, CA: a cancer journal for clinicians.

[67]  D. Rades,et al.  Characterization of Spontaneous and TGF-β-Induced Cell Motility of Primary Human Normal and Neoplastic Mammary Cells In Vitro Using Novel Real-Time Technology , 2013, PloS one.

[68]  Hongbing Shen,et al.  Pathway Analyses Identify TGFBR2 as Potential Breast Cancer Susceptibility Gene: Results from a Consortium Study among Asians , 2012, Cancer Epidemiology, Biomarkers & Prevention.

[69]  H. Lan,et al.  TGF-β/Smad signaling in kidney disease. , 2012, Seminars in nephrology.

[70]  P. Agostinis,et al.  Autophagy in disease: a double-edged sword with therapeutic potential. , 2009, Clinical science.

[71]  R. Weinberg,et al.  Tumour invasion and metastasis initiated by microRNA-10b in breast cancer , 2007, Nature.

[72]  A. Manni,et al.  Growth factor involvement in the multihormonal regulation of MCF-7 breast cancer cell growth in soft agar , 1991, Breast Cancer Research and Treatment.

[73]  Jenny G. Parvani,et al.  The Pathophysiology of Epithelial-Mesenchymal Transition Induced by Transforming Growth Factor-β in Normal and Malignant Mammary Epithelial Cells , 2010, Journal of Mammary Gland Biology and Neoplasia.

[74]  C. Arteaga,et al.  Blockade of TGF-β inhibits mammary tumor cell viability, migration, and metastases , 2002 .

[75]  L. Wakefield,et al.  Lifetime exposure to a soluble TGF-beta antagonist protects mice against metastasis without adverse side effects. , 2002, The Journal of clinical investigation.

[76]  J. Rivera,et al.  Physical activity during the school day in public primary schools in Mexico City. , 2009, Salud publica de Mexico.

[77]  Jian Luo,et al.  Inhibition of breast cancer metastases by a novel inhibitor of TGFβ receptor 1. , 2013, Journal of the National Cancer Institute.

[78]  R. Akhurst,et al.  Complexities of TGF-β Targeted Cancer Therapy , 2012, International journal of biological sciences.

[79]  Michael K. Wendt,et al.  Mechanisms of the epithelial-mesenchymal transition by TGF-beta. , 2009, Future oncology.

[80]  Sha Huang,et al.  Mesenchymal stem cells play a potential role in regulating the establishment and maintenance of epithelial-mesenchymal transition in MCF7 human breast cancer cells by paracrine and induced autocrine TGF-β. , 2012, International journal of oncology.

[81]  Y. Wan,et al.  Transforming Growth Factor-β and the Immune Response: Implications for Anticancer Therapy , 2007, Clinical Cancer Research.

[82]  S. Jakowlew.  Transforming growth factor-β in cancer and metastasis , 2006, Cancer and Metastasis Reviews.

[83]  K. Miyazono,et al.  Regulation of autophagy by transforming growth factor-β (TGF-β) signaling , 2010, Autophagy.

[84]  J. Quigley,et al.  Matrix metalloproteinases and tumor metastasis , 2006, Cancer and Metastasis Reviews.

[85]  R. Crystal,et al.  A SNAIL1–SMAD3/4 transcriptional repressor complex promotes TGF-β mediated epithelial–mesenchymal transition , 2009, Nature Cell Biology.

[86]  Jia-Yun Chen,et al.  TGF-β induces apoptosis through Smad-mediated expression of DAP-kinase , 2002, Nature Cell Biology.

[87]  P. Codogno,et al.  Autophagy Signaling and the Cogwheels of Cancer , 2006, Autophagy.

[88]  M. Thun,et al.  Transforming Growth Factor β Receptor Type I and Transforming Growth Factor β1 Polymorphisms Are Not Associated with Postmenopausal Breast Cancer , 2006, Cancer Epidemiology Biomarkers & Prevention.

[89]  J. Chang-Claude,et al.  A Transforming Growth Factorβ1 Signal Peptide Variant Increases Secretion in Vitro and Is Associated with Increased Incidence of Invasive Breast Cancer , 2003 .

[90]  Jenny G. Parvani,et al.  Noncanonical TGF-β Signaling During Mammary Tumorigenesis , 2011, Journal of Mammary Gland Biology and Neoplasia.

[91]  M. Reiss,et al.  Targeting the Transforming Growth Factor-β pathway inhibits human basal-like breast cancer metastasis , 2010, Molecular Cancer.

[92]  M. Schreiber,et al.  The L10P Polymorphism and Serum Levels of Transforming Growth Factor β1 in Human Breast Cancer , 2013, International journal of molecular sciences.

[93]  B. Paulweber,et al.  The L10P polymorphism of the transforming growth factor-beta 1 gene is not associated with breast cancer risk. , 2003, Cancer letters.

[94]  F. Couch,et al.  No association of TGFB1 L10P genotypes and breast cancer risk in BRCA1 and BRCA2 mutation carriers: a multi-center cohort study , 2009, Breast Cancer Research and Treatment.

[95]  H. Ford,et al.  Gene amplification is a mechanism of Six1 overexpression in breast cancer. , 2005, Cancer research.

[96]  K. Yoshiura,et al.  Transforming growth factor beta1 (TGFβ1) polymorphisms and breast cancer risk , 2014, Tumor Biology.

[97]  C. Heldin,et al.  Mechanism of TGF-beta signaling to growth arrest, apoptosis, and epithelial-mesenchymal transition. , 2009, Current opinion in cell biology.

[98]  W. Schiemann,et al.  Role of TGF-β and the tumor microenvironment during mammary tumorigenesis. , 2011, Gene expression.

[99]  Jenny G. Parvani,et al.  Targeted inactivation of β1 integrin induces β3 integrin switching, which drives breast cancer metastasis by TGF-β , 2013, Molecular biology of the cell.

[100]  Sanford Markowitz,et al.  TGF-β-induced nuclear localization of Smad2 and Smad3 in Smad4 null cancer cell lines , 2003, Oncogene.

[101]  F. Hoffmann,et al.  Inhibition of transforming growth factor-beta1-induced signaling and epithelial-to-mesenchymal transition by the Smad-binding peptide aptamer Trx-SARA. , 2006, Molecular biology of the cell.

[102]  Y. Shyr,et al.  Transgenic mice expressing a dominant-negative mutant type II transforming growth factor-beta receptor exhibit impaired mammary development and enhanced mammary tumor formation. , 2003, The American journal of pathology.

[103]  H. Ford,et al.  Homeoprotein Six1 increases TGF-beta type I receptor and converts TGF-beta signaling from suppressive to supportive for tumor growth. , 2010, Cancer research.

[104]  Nina M. Muñoz,et al.  Targeting TGF-β signaling in cancer , 2013, Expert opinion on therapeutic targets.

[105]  J. Massagué.  TGFβ signalling in context , 2012, Nature Reviews Molecular Cell Biology.

[106]  K. Wagner,et al.  Parity-induced mouse mammary epithelial cells are pluripotent, self-renewing and sensitive to TGF-β1 expression , 2005, Oncogene.

[107]  C. Henderson,et al.  Role of WHO. , 1982, Experientia. Supplementum.

[108]  N. Nagaraj,et al.  Targeting the transforming growth factor-β signaling pathway in human cancer , 2010, Expert opinion on investigational drugs.

[109]  J. Blenis,et al.  Rapamycin inhibits cell motility by suppression of mTOR-mediated S6K1 and 4E-BP1 pathways , 2006, Oncogene.

[110]  K. Miyazono,et al.  Bone morphogenetic protein signaling enhances invasion and bone metastasis of breast cancer cells through Smad pathway , 2008, Oncogene.

[111]  Xin-Hua Feng,et al.  Regulation of TGF-beta signalling by protein phosphatases. , 2010, The Biochemical journal.

[112]  D. Rubinsztein,et al.  Chemical modulators of autophagy as biological probes and potential therapeutics. , 2011, Nature chemical biology.

[113]  L. Wakefield,et al.  Development of oncolytic adenovirus armed with a fusion of soluble transforming growth factor-beta receptor II and human immunoglobulin Fc for breast cancer therapy. , 2006, Human gene therapy.

[114]  M. Barcellos-Hoff,et al.  TGF-beta biology in mammary development and breast cancer. , 2011, Cold Spring Harbor perspectives in biology.

[115]  R. Derynck,et al.  TGFβ‐stimulated Smad1/5 phosphorylation requires the ALK5 L45 loop and mediates the pro‐migratory TGFβ switch , 2009, The EMBO journal.

[116]  X. Shu,et al.  Genetic Polymorphisms of the Transforming Growth Factor-β1 Gene and Breast Cancer Risk: A Possible Dual Role at Different Cancer Stages , 2005, Cancer Epidemiology Biomarkers & Prevention.

[117]  H. Moses,et al.  Transforming growth factor-beta1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. , 2001, Molecular biology of the cell.

[118]  P. Keely,et al.  Breast tumor and stromal cell responses to TGF-β and hypoxia in matrix deposition. , 2013, Matrix biology : journal of the International Society for Matrix Biology.

[119]  Eun-sook Kim,et al.  TGF-beta-induced upregulation of MMP-2 and MMP-9 depends on p38 MAPK, but not ERK signaling in MCF10A human breast epithelial cells. , 2004, International journal of oncology.

[120]  Y. Inoue,et al.  The roles of TGF-β signaling in carcinogenesis and breast cancer metastasis , 2012, Breast Cancer.

[121]  Govind Bhagat,et al.  Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. , 2003, The Journal of clinical investigation.

[122]  J. Downward,et al.  Ras and TGFβ cooperatively regulate epithelial cell plasticity and metastasis , 2002, The Journal of Cell Biology.

[123]  C. Heldin,et al.  Non-Smad TGF-β signals , 2005, Journal of Cell Science.

[124]  G. Tortora,et al.  LY2109761, a novel transforming growth factor β receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis , 2008, Molecular Cancer Therapeutics.

[125]  Brian Bierie,et al.  Transforming growth factor-beta regulates mammary carcinoma cell survival and interaction with the adjacent microenvironment. , 2008, Cancer research.

[126]  T. Shimizu,et al.  Inhibitory effect of a TGFβ receptor type-I inhibitor, Ki26894, on invasiveness of scirrhous gastric cancer cells , 2010, British Journal of Cancer.

[127]  William P Schiemann,et al.  TGF-β upregulates miR-181a expression to promote breast cancer metastasis. , 2013, The Journal of clinical investigation.

[128]  R. Derynck,et al.  Differentiation plasticity regulated by TGF-β family proteins in development and disease , 2007, Nature Cell Biology.

[129]  J. Berzofsky,et al.  An anti-transforming growth factor beta antibody suppresses metastasis via cooperative effects on multiple cell compartments. , 2008, Cancer research.

[130]  H. Ford,et al.  The miR-106b-25 cluster targets Smad7, activates TGF-β signaling, and induces EMT and tumor initiating cell characteristics downstream of Six1 in human breast cancer , 2012, Oncogene.

[131]  S. Rosenberg,et al.  TGF-β1 Attenuates the Acquisition and Expression of Effector Function by Tumor Antigen-Specific Human Memory CD8 T Cells , 2005, The Journal of Immunology.

[132]  D. Cao,et al.  Transforming growth factor-beta signaling in breast cancer. , 2007, Frontiers in bioscience : a journal and virtual library.

[133]  Mari C Sogayar,et al.  TGF-β1 modulates the homeostasis between MMPs and MMP inhibitors through p38 MAPK and ERK1/2 in highly invasive breast cancer cells , 2011, BMC Cancer.

[134]  Kohei Miyazono,et al.  Biology of transforming growth factor-β signaling. , 2011, Current pharmaceutical biotechnology.

[135]  T. Motyl,et al.  Matrix metalloproteinase-2 involvement in breast cancer progression: a mini-review. , 2009, Medical science monitor : international medical journal of experimental and clinical research.

[136]  V. Karantza,et al.  Role of Autophagy in Breast Cancer , 2007, Autophagy.

[137]  P. Dijke,et al.  The TGF-β/Smad pathway induces breast cancer cell invasion through the up-regulation of matrix metalloproteinase 2 and 9 in a spheroid invasion model system , 2011, Breast Cancer Research and Treatment.

[138]  Gerhard Christofori,et al.  Mechanisms of Motility in Metastasizing Cells , 2010, Molecular Cancer Research.

[139]  J. Zarzyńska,et al.  Dissimilar effects of LY 294002 and PD 098059 in IGF-I-mediated inhibition of TGF-beta1 expression and apoptosis in bovine mammary epithelial cells. , 2005, Journal of physiology and pharmacology : an official journal of the Polish Physiological Society.

[140]  Jenny G. Parvani,et al.  The relevance of the TGF-β Paradox to EMT-MET programs. , 2013, Cancer letters.

[141]  Arnold J. Levine,et al.  Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor , 2003, Proceedings of the National Academy of Sciences of the United States of America.