§ 瀏覽學位論文書目資料
  
系統識別號 U0002-1706201117470800
DOI 10.6846/TKU.2011.00580
論文名稱(中文) 3,3'-二吲哚甲烷藉由降低 HER2/neu 誘使 HER2/neu 過表現卵巢癌和乳癌細胞凋亡
論文名稱(英文) 3, 3’-diindolylmethane induces apoptosis through reduction of HER2/neu in HER2/neu-overexpressing ovarian and breast cancers
第三語言論文名稱
校院名稱 淡江大學
系所名稱(中文) 化學學系碩士班
系所名稱(英文) Department of Chemistry
外國學位學校名稱
外國學位學院名稱
外國學位研究所名稱
學年度 99
學期 2
出版年 100
研究生(中文) 梁展帆
研究生(英文) Chan-Fan Liang
學號 697160892
學位類別 碩士
語言別 繁體中文
第二語言別
口試日期 2011-05-19
論文頁數 73頁
口試委員 指導教授 - 莊子超
委員 - 許世忠
委員 - 陳銘凱
關鍵字(中) 神經膠原致癌基因
3, 3'-二吲哚甲烷
關鍵字(英) HER2/neu
3,3'-diindolylmethe
第三語言關鍵字
學科別分類
中文摘要
致癌基因 HER2/neu 過表現導致腫瘤細胞侵入、轉移和血管新生。文獻指出, 3,3’-二吲哚甲烷 (3,3’-diindolylmethane, DIM) 擁有抗癌活性。本實驗證實 DIM 能夠抑制 HER2/neu 表現的卵巢癌和乳癌細胞增生。本實驗結果顯示 DIM 在 HER2/neu 表現的卵巢癌和乳癌細胞中,能抑制 HER2/neu 和其下游 PI3K/Akt 訊號傳遞路徑,因此降低 HER2/neu 誘導的腫瘤轉移能力。此外從 PARP 被切斷的程度顯示 DIM 能促進卵巢癌和乳癌細胞凋亡。總和以上結果,本實驗為 DIM 的抗癌效應提出新的分子機制。
英文摘要
Overexpression of the HER2 oncogene contributes to tumor cell invasion, metastasis and angiogenesis. 3,3’-diindolylmethane (DIM) has been reported to exhibit anti-tumor activities. Here, we examined the anti-proliferating effects of DIM on HER2-positive ovarian and breast cancer cells. Our results demonstrated that DIM may inhibit HER2 and its downstream PI3K/Akt-signaling network, thus resulting in suppression of HER2-mediated metastatic potential in HER2-positive ovarian and breast cancers. Besides, DIM-induced apoptosis in HER2-positive ovarian and breast cancer cells was characterized by the up-regulation of cleaved poly(ADP-ribose) polymerase (PARP). Taken together, our data provide a new mechanism for the DIM-mediated anticancer effect.
第三語言摘要
論文目次
摘要	I
中文摘要	I
英文摘要	II
第一章 緒論	1
第一節 神經膠原致癌基因 (HER2/NEU)	1
第二節 3, 3’-二吲哚甲烷	11
第三節 實驗動機與目的	19
第二章 材料與方法	20
第三章 結果	29
第一節 實驗結果	29
第二節 實驗圖表	35
第四章 討論	46
第五章 參考文獻	49
附錄	68
參考文獻
Abdelrahim M, Newman K, Vanderlaag K, Samudio I, Safe S (2006). 3,3'- diindolylmethane (DIM) and its derivatives induce apoptosis in pancreatic cancer cells through endoplasmic reticulum stress-dependent upregulation of DR5. Carcinogenesis 27: 717-728.

Aggarwal B (2004). Nuclear factor-[kappa] B: The enemy within. Cancer cell 6: 203-208.

Aggarwal B, Ichikawa H (2005). Molecular targets and anticancer potential of indole-3-carbinol and its derivatives. Cell cycle (Georgetown, Tex.) 4: 1201-1215.

Aggarwal B, Shishodia S (2006). Molecular targets of dietary agents for prevention and therapy of cancer. Biochemical pharmacology 71: 1397-1421.

Agus D, Akita R, Fox W, Lewis G, Higgins B, Pisacane P et al (2002). Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer cell 2: 127-137.

Anderton M, Jukes R, Lamb J, Manson M, Gescher A, Steward W et al (2003). Liquid chromatographic assay for the simultaneous determination of indole-3-carbinol and its acid condensation products in plasma. Journal of Chromatography B 787: 281-291.

Anderton M, Manson M, Verschoyle R, Gescher A, Lamb J, Farmer P et al (2004). Pharmacokinetics and tissue disposition of indole-3-carbinol and its acid condensation products after oral administration to mice. Clinical Cancer Research 10: 5233-5241.

Ashcroft M, Ludwig R, Woods D, Copeland T, Weber H, MacRae E et al (2002). Phosphorylation of HDM2 by Akt. Oncogene 21: 1955-1962.

Auborn K, Fan S, Rosen E, Goodwin L, Chandraskaren A, Williams D et al (2003). Indole-3-carbinol is a negative regulator of estrogen. Journal of Nutrition 133: 2470S-2475S.

Bagheri-Yarmand R, Vadlamudi R, Wang R, Mendelsohn J, Kumar R (2000). Vascular endothelial growth factor up-regulation via p21-activated kinase-1 signaling regulates heregulin-β1-mediated angiogenesis. Journal of Biological Chemistry 275: 39451-39457.

Barone M, Crozat A, Tabaee A, Philipson L, Ron D (1994). CHOP (GADD153) and its oncogenic variant, TLS-CHOP, have opposing effects on the induction of G1/S arrest. Genes & development 8: 453-464.

Baselga J, Swain S (2009). Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nature Reviews Cancer 9: 463-475.

Bellacosa A, Kumar C, Cristofano A, Testa J (2005). Activation of AKT kinases in cancer: implications for therapeutic targeting. Advances in Cancer Research 94: 29-86.

Benusiglio P (2008). Focus on ERBB2. Pharmacogenomics 9: 825-828.

Bhatnagar N, Li X, Chen Y, Zhou X, Garrett S, Guo B (2009). 3, 3′-Diindolylmethane enhances the efficacy of butyrate in colon cancer prevention through down-regulation of survivin. Cancer Prevention Research 2: 581-589.

Bhuiyan M, Li Y, Banerjee S, Ahmed F, Wang Z, Ali S et al (2006). Down-regulation of androgen receptor by 3, 3′-diindolylmethane contributes to inhibition of cell proliferation and induction of apoptosis in both hormone-sensitive LNCaP and insensitive C4-2B prostate cancer cells. Cancer research 66: 10064-10072.

Bjeldanes L, Kim J, Grose K, Bartholomew J, Bradfield C (1991). Aromatic hydrocarbon responsiveness-receptor agonists generated from indole-3-carbinol in vitro and in vivo: comparisons with 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin. Proceedings of the National Academy of Sciences of the United States of America 88: 9543-9547.

Bradlow H, Michnovicz J, Telang N, Osborne M (1991). Effects of dietary indole-3-carbinol on estradiol metabolism and spontaneous mammary tumors in mice. Carcinogenesis 12: 1571-1574.

Brandi G, Paiardini M, Cervasi B, Fiorucci C, Filippone P, De Marco C et al (2003). A new indole-3-carbinol tetrameric derivative inhibits cyclin-dependent kinase 6 expression, and induces G1 cell cycle arrest in both estrogen-dependent and estrogen-independent breast cancer cell lines. Cancer research 63: 4028-4036.

Brehm A, Miska E, McCance D, Reid J, Bannister A, Kouzarides T (1998). Retinoblastoma protein recruits histone deacetylase to repress transcription. Nature 391: 597-601.

Burgess A, Cho H, Eigenbrot C, Ferguson K, Garrett T, Leahy D et al (2003). An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Molecular cell 12: 541-552.

Burstein H, Sun Y, Dirix L, Jiang Z, Paridaens R, Tan A et al (2010). Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. Journal of Clinical Oncology 28: 1301-1307.

Cao N, Li S, Wang Z, Ahmed KM et al (2009). NF-
Carter T, Liu K, Ralph Jr W, Chen D, Qi M, Fan S et al (2002). Diindolylmethane
alters gene expression in human keratinocytes in vitro. Journal of Nutrition 132:
3314-3324.
Chambers A, Groom A, MacDonald I (2002). Metastasis: dissemination and growth of
cancer cells in metastatic sites. Nature Reviews Cancer 2: 563-572.
Chambers A, Matrisian L (1997). Changing views of the role of matrix
metalloproteinases in metastasis. Journal of the National Cancer Institute 89:
1260-1270.
Chen Y, Law P, Loh H (2005). Inhibition of PI3K/Akt signaling: an emerging
paradigm for targeted cancer therapy. Current Medicinal Chemistry-Anti-Cancer
Agents 5: 575-589.
Cheng J, Lindsley C, Cheng G, Yang H, Nicosia S (2005). The Akt/PKB pathway:
molecular target for cancer drug discovery. Oncogene 24: 7482-7492.
Chinni S, Li Y, Upadhyay S, Koppolu P, Sarkar F (2001). Indole-3-carbinol (I3C)
induced cell growth inhibition, G1 cell cycle arrest and apoptosis in prostate cancer
cells. Oncogene 20: 2927-2936.
Chinni S, Sarkar F (2002). Akt inactivation is a key event in indole-3-carbinol-induced apoptosis in PC-3 cells. Clinical Cancer Research 8:
1228-1236.
Cho H, Leahy D (2002). Structure of the extracellular region of HER3 reveals an
interdomain tether. Science 297: 1330-1333.
Cho H, Mason K, Ramyar K, Stanley A, Gabelli S, Denney D et al (2003). Structure
of the extracellular region of HER2 alone and in complex with the Herceptin Fab.
Nature 421: 756-760.
Citri A, Gan J, Mosesson Y, Vereb G et al (2004). Hsp90 restrains ErbB-2/HER2
signalling by limiting heterodimer formation. EMBO rep. 5: 1165-1170
Cohen J, Kristal A, Stanford J (2000). Fruit and vegetable intakes and prostate cancer
risk. JNCI Journal of the National Cancer Institute 92: 61-68.
Cornolti G, Ungari M, Morassi M, Facchetti F, Rossi E, Lombardi D et al (2007).
Amplification and overexpression of HER2/neu gene and HER2/neu protein in
salivary duct carcinoma of the parotid gland. Archives of Otolaryngology- Head and
Neck Surgery 133: 1031-1036.
Cover C, Hsieh S, Tran S, Hallden G, Kim G, Bjeldanes L et al (1998).
Indole-3-carbinol inhibits the expression of cyclin-dependent kinase-6 and induces a
G1 cell cycle arrest of human breast cancer cells independent of estrogen receptor
signaling. Journal of Biological Chemistry 273: 3838-3847.
Cram E, Liu B, Bjeldanes L, Firestone G (2001). Indole-3-carbinol inhibits CDK6
expression in human MCF-7 breast cancer cells by disrupting Sp1 transcription factor
interactions with a composite element in the CDK6 gene promoter. Journal of
Biological Chemistry 276: 22332-22340.
D'souza B, Taylor-Papadimitriou J (1994). Overexpression of ERBB2 in human
mammary epithelial cells signals inhibition of transcription of the E-cadherin gene.
Proceedings of the National Academy of Sciences of the United States of America 91:
7202-7206.
Dashwood R (1998). Indole-3-carbinol: anticarcinogen or tumor promoter in brassica
vegetables? Chemico-biological interactions 110: 1-5.
Datta S, Dudek H, Tao X, Masters S, Fu H, Gotoh Y et al (1997). Akt phosphorylation
of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91:
231-241.
De Kruif C, Marsman J, Venekamp J, Falke H, Noordhoek J, Blaauboer B et al (1991).
Structure elucidation of acid reaction products of indole-3-carbinol: detection in vivo
and enzyme induction in vitro. Chemico-biological interactions 80: 303-315.
Dhillon A, Hagan S, Rath O, Kolch W (2007). MAP kinase signalling pathways in
cancer. Oncogene 26: 3279-3290.
Eccles S (2001). The role of c-erbB-2/HER2/neu in breast cancer progression and
metastasis. Journal of mammary gland biology and neoplasia 6: 393-406.
Eferl R, Wagner E (2003). AP-1: a double-edged sword in tumorigenesis. Nature
Reviews Cancer 3: 859-868.
Fan S, Meng Q, Auborn K, Carter T, Rosen E (2006). BRCA1 and BRCA2 as
molecular targets for phytochemicals indole-3-carbinol and genistein in breast and
prostate cancer cells. British journal of cancer 94: 407-426.
Ferguson K, Berger M, Mendrola J, Cho H, Leahy D, Lemmon M (2003). EGF
activates its receptor by removing interactions that autoinhibit ectodomain
dimerization. Molecular cell 11: 507-517.
Fernandez-Capetillo O, Nussenzweig A (2004). Linking histone deacetylation with
the repair of DNA breaks. Proceedings of the National Academy of Sciences of the
United States of America 101: 1427-1428.
Firestone G, Bjeldanes L (2003). Indole-3-carbinol and 3-3'-diindolylmethane
antiproliferative signaling pathways control cell-cycle gene transcription in human
breast cancer cells by regulating promoter-Sp1 transcription factor interactions.
Journal of Nutrition 133: 2448S-2455S.
Frame S, Cohen P (2001). GSK3 takes centre stage more than 20 years after its
discovery. Biochemical Journal 359: 1-16.
Franklin M, Carey K, Vajdos F, Leahy D, de Vos A, Sliwkowski M (2004). Insights
54
into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer cell
5: 317-328.
Frydoonfar H, McGrath D, Spigelman A (2002). Inhibition of proliferation of a colon
cancer cell line by indole 3 carbinol. Colorectal Disease 4: 205-207.
Frydoonfar H, McGrath D, Spigelman A (2003). The effect of indole-3-carbinol and
sulforaphane on a prostate cancer cell line. ANZ Journal of Surgery 73: 154-156.
Garcia H, Brar G, Nguyen D, Bjeldanes L, Firestone G (2005). Indole-3-carbinol (I3C)
inhibits cyclin-dependent kinase-2 function in human breast cancer cells by regulating
the size distribution, associated cyclin E forms, and subcellular localization of the
CDK2 protein complex. Journal of Biological Chemistry 280: 8756-8764.
Garikapaty V, Ashok B, Tadi K, Mittelman A, Tiwari R (2006). 3,
3'-Diindolylmethane downregulates pro-survival pathway in hormone independent
prostate cancer. Biochemical and biophysical research communications 340: 718-725.
Gong Y, Xue L, Firestone GL, Bjeldanes LF (2006). 3,3'-Diindolylmethane is a novel
mitochondrial H(+)-ATP synthase inhibitor that can induce p21(Cip1/Waf1)
expression by induction of oxidative stress in human breast cancer cells. Cancer
Research 66: 4880-4887.
Grose K, Bjeldanes L (1992). Oligomerization of indole-3-carbinol in aqueous acid.
Chemical research in toxicology 5: 188-193.
Grunstein M (1997). Histone acetylation in chromatin structure and transcription.
Nature 389: 349-352.
Hellyer N, Cheng K, Koland J (1998). ErbB3 (HER3) interaction with the p85
regulatory subunit of phosphoinositide 3-kinase. Biochemical Journal 333: 757-763.
Hennessy B, Smith D, Ram P, Lu Y, Mills G (2005). Exploiting the PI3K/AKT
pathway for cancer drug discovery. Nature Reviews Drug Discovery 4: 988-1004.
Herrmann S, Seidelin M, Bisgaard H, Vang O (2002). Indolo [3, 2-b] carbazole
inhibits gap junctional intercellular communication in rat primary hepatocytes and
acts as a potential tumor promoter. Carcinogenesis 23: 1861-1868.
55
Higdon J, Delage B, Williams D, Dashwood R (2007). Cruciferous vegetables and
human cancer risk: epidemiologic evidence and mechanistic basis. Pharmacological
research 55: 224-236.
Hong C, Firestone G, Bjeldanes L (2002). Bcl-2 family-mediated apoptotic effects of
3, 3'-diindolylmethane (DIM) in human breast cancer cells. Biochemical
pharmacology 63: 1085-1097.
Hong C, Kim H (2002). 3, 3'-Diindolylmethane (DIM) induces a G1 cell cycle arrest
in human breast cancer cells that is accompanied by Sp1-mediated activation of
p21WAF1/CIP1 expression. Carcinogenesis 23: 1297-1305.
Howells L, Gallacher-Horley B, Houghton C, Manson M, Hudson E (2002).
Indole-3-carbinol inhibits protein kinase B/Akt and induces apoptosis in the human
breast tumor cell line MDA MB468 but not in the nontumorigenic HBL100 line.
Molecular cancer therapeutics 1: 1161-1172.
Hubbard S (2006). EGF receptor activation: push comes to shove. Cell 125:
1029-1031.
Hudson E, Howells L, Gallacher-Horley B, Fox L, Gescher A, Manson M (2003).
Growth-inhibitory effects of the chemopreventive agent indole-3-carbinol are
increased in combination with the polyamine putrescine in the SW 480 colon tumour
cell line. BMC cancer 3: 2-19.
Hynes N, MacDonald G (2009). ErbB receptors and signaling pathways in cancer.
Current opinion in cell biology 21: 177-184.
Izumi Y, Xu L, Di Tomaso E, Fukumura D, Jain R (2002). Tumour biology: herceptin
acts as an anti-angiogenic cocktail. Nature 416: 279-280.
Jaehne J, Urmacher C, Thaler H, Friedlander-Klar H, Cordon-Cardo C, Meyer H
(1992). Expression ofHer2/neu oncogene product p185 in correlation to
clinicopathological and prognostic factors of gastric carcinoma. Journal of cancer
research and clinical oncology 118: 474-479.
Jeon K, Rih J, Kim H, Lee Y, Cho C, Goldberg I et al (2003). Pretreatment of
56
indole-3-carbinol augments TRAIL-induced apoptosis in a prostate cancer cell line,
LNCaP. FEBS letters 544: 246-251.
Karin M, Ben-Neriah Y (2000). Phosphorylation meets ubiquitination: the control of
NF-κB activity. Annual Review of Immunology 18: 621-663.
Katdare M, Osborne M, Telang N (1998). Inhibition of aberrant proliferation and
induction of apoptosis in pre-neoplastic human mammary epithelial cells by natural
phytochemicals. Oncology reports 5: 311-315.
Kaufman R (1999). Stress signaling from the lumen of the endoplasmic reticulum:
coordination of gene transcriptional and translational controls. Genes & development
13: 1211-1233.
Khwaja FS, Wynne S, Posey I, Djakiew D (2009). 3,3'-diindolylmethane induction of
p75NTR-dependent cell death via the p38 mitogen-activated protein kinase pathway
in prostate cancer cells. Cancer Prev Res (Phila). 2: 566-571.
Kim D, Cheng G, Lindsley C, Yang H, Cheng J (2005). Targeting the
phosphatidylinositol-3 kinase/Akt pathway for the treatment of cancer. Current
opinion in investigational drugs (London, England: 2000) 6: 1250-1258.
Kim I, Yong H, Kang K, Moon A (2009). Overexpression of ErbB2 induces invasion
of MCF10A human breast epithelial cells via MMP-9. Cancer letters 275: 227-233.
Kim Y, Milner J (2005). Targets for indole-3-carbinol in cancer prevention. The
Journal of Nutritional Biochemistry 16: 65-73.
Klos KS, Wyszomierski SL, Sun M, Tan M et al (2006). ErbB2 Increases Vascular
Endothelial Growth Factor Protein Synthesis via Activation of Mammalian Target of
Rapamycin/p70S6K Leading to Increased Angiogenesis and Spontaneous Metastasis
of Human Breast Cancer Cells. Cancer research 66: 2028-2037.
Kohle C, Bock K (2007). Coordinate regulation of Phase I and II xenobiotic
metabolisms by the Ah receptor and Nrf2. Biochemical pharmacology 73: 1853-1862.
Konecny G, Pegram M, Venkatesan N, Finn R, Yang G, Rahmeh M et al (2006).
Activity of the dual kinase inhibitor lapatinib (GW572016) against
57
HER-2-overexpressing and trastuzumab-treated breast cancer cells. Cancer research
66: 1630-1639.
Kong D, Banerjee S, Huang W, Li Y, Wang Z, Kim H et al (2008). Mammalian Target
of Rapamycin Repression by 3, 3“-Diindolylmethane Inhibits Invasion and
Angiogenesis in Platelet-Derived Growth Factor-D–Overexpressing PC3 Cells.
Cancer research 68: 1927-1934.
Kong D, Li Y, Wang Z, Banerjee S, Sarkar F (2007). Inhibition of angiogenesis and
invasion by 3, 30-diindolylmethane is mediated by the nuclear factor-kappaB
downstream target genes MMP-9 and uPA that regulated bioavailability of vascular
endothelial growth factor in prostate cancer. Cancer Research 67: 3310-3319.
Kucharczak J, Simmons M, Fan Y, Gelinas C (2003). To be, or not to be: NF-kB is the
answer-role of Rel/NF-kB in the regulation of apoptosis. Oncogene 22: 8961-8982.
Lane H, Beuvink I, Motoyama A, Daly J, Neve R, Hynes N (2000). ErbB2 potentiates
breast tumor proliferation through modulation of p27Kip1-Cdk2 complex formation:
receptor overexpression does not determine growth dependency. Molecular and
cellular biology 20: 3210-3223.
Larsen-Su S, Williams D (2001). Transplacental exposure to indole-3-carbinol
induces sex-specific expression of CYP1A1 and CYP1B1 in the liver of Fischer 344
neonatal rats. Toxicological Sciences 64: 162-168.
Lattrich C, Juhasz-Boess I, Ortmann O, Treeck O (2008). Detection of an elevated
HER2 expression in MCF-7 breast cancer cells overexpressing estrogen receptor
beta1. Oncol Rep 19: 811-817.
Le X, Claret F, Lammayot A, Tian L, Deshpande D, LaPushin R et al (2003). The role
of cyclin-dependent kinase inhibitor p27Kip1 in anti-HER2 antibody-induced G1 cell
cycle arrest and tumor growth inhibition. Journal of Biological Chemistry 278:
23441-233450.
Leong H, Firestone G, Bjeldanes L (2001). Cytostatic effects of 3, 3'-diindolylmethane
in human endometrial cancer cells result from an estrogen receptor-mediated increase
in transforming growth factor-{alpha} expression. Carcinogenesis 22: 1809-1817.
58
Li Y, Li X, Guo B (2010). Chemopreventive Agent 3, 3“-Diindolylmethane
Selectively Induces Proteasomal Degradation of Class I Histone Deacetylases. Cancer
research 70: 646-654.
Li Y, Li X, Sarkar F (2003). Gene expression profiles of I3C-and DIM-treated PC3
human prostate cancer cells determined by cDNA microarray analysis. Journal of
Nutrition 133: 1011-1019.
Li Y, Wang Z, Kong D, Murthy S, Dou Q, Sheng S et al (2007). Regulation of
FOXO3a/℃-catenin/GSK-3℃ signaling by 3, 3“-diindolylmethane contributes to
inhibition of cell proliferation and induction of apoptosis in prostate cancer cells.
Journal of Biological Chemistry 282: 21542-21550.
Lian J, Word B, Taylor S, Hammons G, Lyn-Cook B (2004). Modulation of the
constitutive activated STAT3 transcription factor in pancreatic cancer prevention:
effects of indole-3-carbinol (I3C) and genistein. Anticancer research 24: 133-137.
Liu E, Thor A, He M, Barcos M, Ljung B, Benz C (1992). The HER2 (c-erbB-2)
oncogene is frequently amplified in in situ carcinomas of the breast. Oncogene 7:
1027-1032.
Liu H, Wormke M, Safe S (1994). Indolo [3, 2-b] carbazole: a dietary-derived factor
that exhibits both antiestrogenic and estrogenic activity. Journal of the National
Cancer Institute 86: 1758-1765.
Lokker N, Sullivan C, Hollenbach S, Israel M, Giese N (2002). Platelet-derived
growth factor (PDGF) autocrine signaling regulates survival and mitogenic pathways
in glioblastoma cells. Cancer research 62: 3729-3735.
Longva K, Pedersen N, Haslekas C, Stang E, Madshus I (2005). Herceptin induced
inhibition of ErbB2 signaling involves reduced phosphorylation of Akt but not
endocytic down regulation of ErbB2. International Journal of Cancer 116: 359-367.
Luo R, Postigo A, Dean D (1998). Rb interacts with histone deacetylase to repress
transcription. Cell 92: 463-473.
Marciniak S, Ron D (2006). Endoplasmic reticulum stress signaling in disease.
Physiological reviews 86: 1133-1149.
Marks P, Rifkind R, Richon V, Breslow R, Miller T, Kelly W (2001). Histone
deacetylases and cancer: causes and therapies. Nature Reviews Cancer 1: 194-202.
McGuire K, Ngoubilly N, Neavyn M, Lanza-Jacoby S (2006). 3, 3'-diindolylmethane
and paclitaxel act synergistically to promote apoptosis in HER2/Neu human breast
cancer cells. J Surg Res 132: 208-213.
Mendelsohn J, Baselga J (2003). Status of epidermal growth factor receptor
antagonists in the biology and treatment of cancer. Journal of Clinical Oncology 21:
2787-1799.
Minella A, Clurman B (2005). Mechanisms of tumor suppression by the SCF (Fbw7).
Cell cycle (Georgetown, Tex.) 4: 1356-1359.
Minich D, Bland J (2007). A review of the clinical efficacy and safety of cruciferous
vegetable phytochemicals. Nutrition reviews 65: 259-267.
Molina M, Codony-Servat J, Albanell J, Rojo F, Arribas J, Baselga J (2001).
Trastuzumab (herceptin), a humanized anti-Her2 receptor monoclonal antibody,
inhibits basal and activated Her2 ectodomain cleavage in breast cancer cells. Cancer
research 61: 4744-4749.
Mulvey L, Chandrasekaran A, Liu K, Lombardi S, Wang X, Auborn K et al (2007).
Interplay of genes regulated by estrogen and diindolylmethane in breast cancer cell
lines. Molecular Medicine 13: 69-78.
Murphy L, MacKeigan J, Blenis J (2004). A network of immediate early gene
products propagates subtle differences in mitogen-activated protein kinase signal
amplitude and duration. Molecular and cellular biology 24: 144-153.
Murphy L, Smith S, Chen R, Fingar D, Blenis J (2002). Molecular interpretation of
ERK signal duration by immediate early gene products. Nature cell biology 4:
556-564.
Nachshon-Kedmi M, Yannai S, Fares F (2004). Induction of apoptosis in human
prostate cancer cell line, PC3, by 3, 3“-diindolylmethane through the mitochondrial
pathway. British journal of cancer 91: 1358-1363.
60
Nachshon-Kedmi M, Yannai S, Haj A, Fares F (2003). Indole-3-carbinol and 3,
30-diindolylmethane induce apoptosis in human prostate cancer cells. Food Chem
Toxicol 41: 745-52.
Nagata Y, Lan K, Zhou X, Tan M, Esteva F, Sahin A et al (2004). PTEN activation
contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts
trastuzumab resistance in patients. Cancer cell 6: 117-127.
Narlikar G, Fan H, Kingston R (2002). Cooperation between complexes that regulate
chromatin structure and transcription. Cell 108: 475-487.
Nechushtan A, Smith C, Yi-Te Hsu R (1999). Conformation of the Bax C-terminus
regulates subcellular location and cell death. The EMBO journal 18: 2330-2341.
Niu G, Carter WB (2007). Human epidermal growth factor receptor 2 regulates
angiopoietin-2 expression in breast cancer via AKT and mitogen-activated protein
kinase pathways. Cancer research 67: 1487-1493.
Ociepa-Zawal M, Rubis B, Lacinski M, Trzeciak W (2007). The effect of
indole-3-carbinol on the expression of CYP1A1, CYP1B1 and AhR genes and
proliferation of MCF-7 cells. Acta Biochim Pol 54: 113-117.
Ogawara Y, Kishishita S, Obata T, Isazawa Y, Suzuki T, Tanaka K et al (2002). Akt
enhances Mdm2-mediated ubiquitination and degradation of p53. Journal of
Biological Chemistry 277: 21843-21850.
Ogiso H, Ishitani R, Nureki O, Fukai S, Yamanaka M, Kim J et al (2002). Crystal
structure of the complex of human epidermal growth factor and receptor extracellular
domains. Cell 110: 775-787.
Olayioye M, Neve R, Lane H, Hynes N (2000). NEW EMBO MEMBERS'REVIEW:
The ErbB signaling network: receptor heterodimerization in development and cancer.
Science's STKE 19: 3159-3167.
Owens M, Horten B, Da Silva M (2004). HER2 amplification ratios by fluorescence
in situ hybridization and correlation with immunohistochemistry in a cohort of 6556
breast cancer tissues. Clinical Breast Cancer 5: 63-69.
61
Park K, Han S, Kim H, Kim J, Shin E (2006). HER2 status in pure ductal carcinoma
in situ and in the intraductal and invasive components of invasive ductal carcinoma
determined by fluorescence in situ hybridization and immunohistochemistry.
Histopathology 48: 702-707.
Parkin D, Malejka-Giganti D (2004). Differences in the hepatic P450-dependent
metabolism of estrogen and tamoxifen in response to treatment of rats with 3,
3'-diindolylmethane and its parent compound indole-3-carbinol. Cancer detection and
prevention 28: 72-79.
Pinkas-Kramarski R, Soussan L, Waterman H, Levkowitz G, Alroy I, Klapper L et al
(1996). Diversification of Neu differentiation factor and epidermal growth factor
signaling by combinatorial receptor interactions. The EMBO journal 15: 2452.-2467
Pratt W, Toft D (2003). Regulation of signaling protein function and trafficking by the
hsp90/hsp70-based chaperone machinery. Experimental biology and medicine
(Maywood, NJ) 228: 111-133.
Prigent S, Gullick W (1994). Identification of c-erbB-3 binding sites for
phosphatidylinositol 3'-kinase and SHC using an EGF receptor/c-erbB-3 chimera. The
EMBO journal 13: 2831-2841.
Rahman K, Ali S, Aboukameel A, Sarkar S, Wang Z, Philip P et al (2007).
Inactivation of NF-κB by 3, 3“-diindolylmethane contributes to increased apoptosis
induced by chemotherapeutic agent in breast cancer cells. Molecular cancer
therapeutics 6: 2757-2765.
Rahman K, Aranha O, Sarkar F (2003). Indole-3-carbinol (I3C) induces apoptosis in
tumorigenic but not in nontumorigenic breast epithelial cells. Nutrition and cancer 45:
101-112.
Rahman K, Li Y, Wang Z, Sarkar S, Sarkar F (2006). Gene expression profiling
revealed survivin as a target of 3, 3“-diindolylmethane-induced cell growth
inhibition and apoptosis in breast cancer cells. Cancer research 66: 4952-4960.
Rahman K, Sarkar F (2005). Inhibition of nuclear translocation of nuclear factor-℃B
contributes to 3, 3“-diindolylmethane-induced apoptosis in breast cancer cells.
Cancer research 65: 364-371.
62
Rajoria S, Suriano R, Wilson YL, Schantz SP (2010). 3,3'-Diindolylmethane inhibits
migration and invasion of human cancer cells through combined suppression of ERK
and AKT pathways. Oncol Rep 25: 491-497.
Rao R, Ellerby H, Bredesen D (2004). Coupling endoplasmic reticulum stress to the
cell death program. Cell Death & Differentiation 11: 372-380.
Reed G, Arneson D, Putnam W, Smith H, Gray J, Sullivan D et al (2006). Single-dose
and multiple-dose administration of indole-3-carbinol to women: pharmacokinetics
based on 3, 3“-diindolylmethane. Cancer Epidemiology Biomarkers & Prevention
15: 2477-2481.
Rogan EG (2006). The natural chemopreventive compound indole-3-carbinol: state of
the science. In Vivo 20: 221-228.
Ross J, Fletcher J (1998). The HER 2/neu Oncogene in Breast Cancer: Prognostic
Factor, Predictive Factor, and Target for Therapy. Stem Cells 16: 413-428.
Rusnak D, Lackey K, Affleck K, Wood E, Alligood K, Rhodes N et al (2001). The
effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine
kinase inhibitor, GW2016, on the growth of human normal and tumor-derived cell
lines in vitro and in vivo. Molecular cancer therapeutics 1: 85-94.
Sarkar F, Li Y (2004). Indole-3-carbinol and prostate cancer. Journal of Nutrition 134:
3493S-3498S.
Sato A, Fujita N, Tsuruo T (2000). Modulation of Akt kinase activity by binding to
Hsp90. Proceedings of the National Academy of Sciences of the United States of
America 97: 10832-10837.
Schechter A, Stern D, Vaidyanathan L, Decker S, Drebin J, Greene M et al (1984).
The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen.
Nature 312: 513-516.
Schulte T, Neckers L (1998). The benzoquinone ansamycin
17-allylamino-17-demethoxygeldanamycin binds to HSP90 and shares important
biologic activities with geldanamycin. Cancer chemotherapy and pharmacology 42:
63
273-279.
Shaw R, Cantley L (2006). Ras, PI (3) K and mTOR signalling controls tumour cell
growth. Nature 441: 424-430.
Shibata T, Ochiai A, Kanai Y, Akimoto S, Gotoh M, Yasui N et al (1996). Dominant
negative inhibition of the association between beta-catenin and c-erbB-2 by
N-terminally deleted beta-catenin suppresses the invasion and metastasis of cancer
cells. Oncogene 13: 883-889.
Slamon D, Clark G, Wong S, Levin W, Ullrich A, McGuire W (1987). Human breast
cancer: correlation of relapse and survival with amplification of the HER-2/neu
oncogene. Science 235: 177-182.
Spector N, Xia W, Burris H, Hurwitz H, Dees E, Dowlati A et al (2005). Study of the
biologic effects of lapatinib, a reversible inhibitor of ErbB1 and ErbB2 tyrosine
kinases, on tumor growth and survival pathways in patients with advanced
malignancies. Journal of Clinical Oncology 23: 2502-2512.
Stiles B (2009). PI-3-K and AKT: Onto the mitochondria. Advanced drug delivery
reviews 61: 1276-1282.
Stresser D, Williams D, Griffin D, Bailey G (1995). Mechanisms of tumor modulation
by indole-3-carbinol. Disposition and excretion in male Fischer 344 rats. Drug
Metabolism and Disposition 23: 965-975.
Sun S, Han J, Ralph Jr W, Chandrasekaran A, Liu K, Auborn K et al (2004).
Endoplasmic reticulum stress as a correlate of cytotoxicity in human tumor cells
exposed to diindolylmethane in vitro. Cell stress & chaperones 9: 76-87.
Sundar S, Kerekatte V, Equinozio C, Doan V, Bjeldanes L, Firestone G (2006).
Indole-3-carbinol selectively uncouples expression and activity of estrogen receptor
subtypes in human breast cancer cells. Molecular Endocrinology 20: 3070-3782.
Takada Y, Andreeff M, Aggarwal B (2005). Indole-3-carbinol suppresses NF-{kappa}
B and I {kappa} B {alpha} kinase activation, causing inhibition of expression of
NF-{kappa} B-regulated antiapoptotic and metastatic gene products and enhancement
of apoptosis in myeloid and leukemia cells. Blood 106: 641-649.
64
Takeuchi K, Ito F (2010). EGF receptor in relation to tumor development: molecular
basis of responsiveness of cancer cells to EGFR targeting tyrosine kinase inhibitors.
FEBS Journal 277: 316-326.
Tzahar E, Waterman H, Chen X, Levkowitz G, Karunagaran D, Lavi S et al (1996). A
hierarchical network of interreceptor interactions determines signal transduction by
Neu differentiation factor/neuregulin and epidermal growth factor. Molecular and
cellular biology 16: 5276-5287.
Ustach C, Kim H (2005). Platelet-derived growth factor D is activated by urokinase
plasminogen activator in prostate carcinoma cells. Molecular and cellular biology 25:
6279-6288.
Ustach C, Taube M, Hurst N, Bhagat S, Bonfil R, Cher M et al (2004). A potential
oncogenic activity of platelet-derived growth factor d in prostate cancer progression.
Cancer research 64: 1722-1729.
Van Laethem A, Van Kelst S, Lippens S, Declercq W, Vandenabeele P, Janssens S et
al (2004). Activation of p38 MAPK is required for Bax translocation to mitochondria,
cytochrome c release and apoptosis induced by UVB irradiation in human
keratinocytes. The FASEB Journal 18: 1946-1948.
Verhoeven D, Goldbohm R, van Poppel G, Verhagen H, van den Brandt P (1996).
Epidemiological studies on brassica vegetables and cancer risk. Cancer Epidemiology
Biomarkers & Prevention 5: 733-748.
Vermeij J, Teugels E, Bourgain C, Xiangming J (2008). Genomic activation of the
EGFR and HER2-neu genes in a significant proportion of invasive epithelial ovarian
cancers. BMC cancer 8: 3-11.
Vivar OI, Lin CL, Firestone GL, Bjeldanes LF (2009). 3,3'-Diindolylmethane induces
a G(1) arrest in human prostate cancer cells irrespective of androgen receptor and p53
status. Biochem Pharmacol.78: 469-476.
Wagner E, Nebreda A (2009). Signal integration by JNK and p38 MAPK pathways in
cancer development. Nature Reviews Cancer 9: 537-549.
Wang T, Milner M, Milner J, Kim Y (2006). Estrogen receptor [alpha] as a target for
indole-3-carbinol. The Journal of Nutritional Biochemistry 17: 659-664.
Wang Z, Ahmad A, Li Y, Kong D, Azmi A, Banerjee S et al (2010). Emerging roles of
PDGF-D signaling pathway in tumor development and progression. Biochimica et
Biophysica Acta 1806: 122-130.
Wang Z, Kong D, Banerjee S, Li Y, Adsay N, Abbruzzese J et al (2007).
Down-regulation of Platelet-Derived Growth Factor-D Inhibits Cell Growth and
Angiogenesis through Inactivation of Notch-1 and Nuclear Factor-κB Signaling.
Cancer research 67: 11377-11385.
Weng J, Tsai C, Kulp S, Chen C (2008). Indole-3-carbinol as a chemopreventive and
anti-cancer agent. Cancer letters 262: 153-163.
Weng J, Tsai C, Kulp S, Wang D, Lin C, Yang H et al (2007). A Potent
Indole-3-Carbinol–Derived Antitumor Agent with Pleiotropic Effects on Multiple
Signaling Pathways in Prostate Cancer Cells. Cancer research 67: 7815-7824.
Weston C, Davis R (2002). The JNK signal transduction pathway. Current opinion in
genetics & development 12: 14-21.
Wilson A, Byun D, Popova N, Murray L, L'Italien K, Sowa Y et al (2006). Histone
deacetylase 3 (HDAC3) and other class I HDACs regulate colon cell maturation and
p21 expression and are deregulated in human colon cancer. Journal of Biological
Chemistry 281: 13548-13558.
Xia W, Mullin R, Keith B, Liu L, Ma H, Rusnak D et al (2002). Anti-tumor activity of
GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2
and downstream Erkl/2 and AKT pathways. Oncogene 21: 6255-6263.
Xin M, Deng X (2005). Nicotine inactivation of the proapoptotic function of Bax
through phosphorylation. Journal of Biological Chemistry 280: 10781.
Xiong S, Grijalva R, Zhang L, Nguyen N, Pisters P, Pollock R et al (2001).
Up-regulation of vascular endothelial growth factor in breast cancer cells by the
heregulin-β1-activated p38 signaling pathway enhances endothelial cell migration.
Cancer research 61: 1727-1732.
66
Xu L, Tong R, Cochran D, Jain R (2005). Blocking platelet-derived growth
factor-D/platelet-derived growth factor receptor β signaling inhibits human renal cell
carcinoma progression in an orthotopic mouse model. Cancer research 65:
5711-5719.
Xue L, Firestone GL, Bjeldanes LF (2005). DIM stimulates IFNgamma gene
expression in human breast cancer cells via the specific activation of JNK and p38
pathways. Oncogene 24: 2343-2353
Yamaguchi H, Wang H (2001). The protein kinase PKB/Akt regulates cell survival
and apoptosis by inhibiting Bax conformational change. Oncogene 20: 7779-7786.
Yarden Y, Sliwkowski M (2001). Untangling the ErbB signalling network. Nature
Reviews Molecular Cell Biology 2: 127-137.
Yaziji H, Goldstein L, Barry T, Werling R, Hwang H, Ellis G et al (2004). HER-2
testing in breast cancer using parallel tissue-based methods. Jama 291: 1972-1977.
Yoeli-Lerner M, Toker A (2006). Akt/PKB signaling in cancer: a function in cell
motility and invasion. Cell cycle 5: 603-605.
Yoon S, Seger R (2006). The extracellular signal-regulated kinase: multiple substrates
regulate diverse cellular functions. Growth Factors 24: 21-44.
Yu D, Hamada J, HONG Z, Nicolson G (1992). Mechanisms of c-erbB2/neu
oncogene-induced metastasis and repression of metastatic properties by adenovirus 5
E1A gene products. Oncogene 7: 2263-2270.
Yu D, Hung M (2000). Overexpression of ErbB2 in cancer and ErbB2-targeting
strategies. Oncogene 19: 6115-6121.
Zhang X, Gureasko J, Shen K, Cole P, Kuriyan J (2006). An allosteric mechanism for
activation of the kinase domain of epidermal growth factor receptor. Cell 125:
1137-1149.
Zheng F, Kuduk S, Chiosis G, Munster P, Sepp-Lorenzino L, Danishefsky S et al
(2000). Identification of a geldanamycin dimer that induces the selective degradation
67
of HER-family tyrosine kinases. Cancer research 60: 2090-2094.
Zheng Q, Hirose Y, Yoshimi N, Murakami A, Koshimizu K, Ohigashi H et al (2002).
Further investigation of the modifying effect of various chemopreventive agents on
apoptosis and cell proliferation in human colon cancer cells. Journal of cancer
research and clinical oncology 128: 539-546.
Zuo T, Wang L, Morrison C, Chang X, Zhang H, Li W et al (2007). FOXP3 is an
X-linked breast cancer suppressor gene and an important repressor of the
HER-2/ErbB2 oncogene. Cell 129: 1275-1286.
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