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Breast Cancer Research
Published in: Breast Cancer Research 3/2009

Open Access 01-06-2009 | Research article

PI-3 kinase activity is necessary for ERK1/2-induced disruption of mammary epithelial architecture

Authors: Gray W Pearson, Tony Hunter

Published in: Breast Cancer Research | Issue 3/2009

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Abstract

Introduction

Epithelial tumors, including breast cancer, are being identified and treated at earlier stages of tumor development because of technological advances in screening and detection methods. It is likely that early-stage epithelial tumors, such as mammary ductal carcinoma in situ (DCIS), will be amenable to new and more efficacious diagnostic tests and forms of therapy. However, our limited understanding of the underlying molecular mechanisms of early-stage epithelial tumor growth has hampered the development of new forms treatment and preventative therapy.

Methods

The Raf–MEK1/2–ERK1/2 mitogen-activated protein kinase module is activated by stimuli complicit in mammary neoplastic progression. We have recently demonstrated that the activation of ERK1/2 induces a non-invasive form of motility, where cells can track along the basement membrane and adjacent epithelial cells, but do not become invasive over time, using real-time imaging of a mammary epithelial organotypic culture model. Using this novel approach combined with traditional biochemical techniques, we have analyzed at the molecular level how ERK1/2 induces this new non-invasive form of motility as well as proliferation and cell survival.

Results

We find that the activation of Raf:ER in the differentiated epithelium of fully formed acini promotes proliferation and cell survival, which are characteristic features of pre-invasive DCIS lesions. The activation of ERK1/2 correlated with induction of c-Fos, a transcriptional regulator of proliferation and reduced expression of the pro-apoptotic BH3-only protein BIM. Both ERK1/2 and PI-3 kinase-dependent effector pathways were required for activated Raf:ER to reduce expression of p27 and promote proliferation. In addition, PI-3K activity was necessary for the induction of non-invasive motility induced by ERK1/2.

Conclusions

ERK1/2 activation is sufficient to induce cell behaviors in organotypic culture that could promote recurrent and invasive growth in DCIS patients. Interestingly, PI-3K activity is necessary for two of these behaviors, proliferation and cell motility. Collectively, our results suggest that the relationship between the activity state of the ERK1/2 and PI-3K signaling pathways and recurrent growth in DCIS patients should be investigated.
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Literature
1.
Li CI, Daling JR, Malone KE: Age-specific incidence rates of in situ breast carcinomas by histologic type, 1980 to 2001. Cancer Epidemiol Biomarkers Prev. 2005, 14: 1008-1011.CrossRefPubMed
2.
3.
Allred DC, Mohsin SK, Fuqua SA: Histological and biological evolution of human premalignant breast disease. Endocr Relat Cancer. 2001, 8: 47-61.CrossRefPubMed
4.
Burstein HJ, Polyak K, Wong JS, Lester SC, Kaelin CM: Ductal carcinoma in situ of the breast. N Engl J Med. 2004, 350: 1430-1441.CrossRefPubMed
5.
Wood LD, Parsons DW, Jones S, Lin J, Sjoblom T, Leary RJ, Shen D, Boca SM, Barber T, Ptak J, Silliman N, Szabo S, Dezso Z, Ustyanksky V, Nikolskaya T, Nikolsky Y, Karchin R, Wilson PA, Kaminker JS, Zhang Z, Croshaw R, Willis J, Dawson D, Shipitsin M, Willson JK, Sukumar S, Polyak K, Park BH, Pethiyagoda CL, Pant PV, et al: The genomic landscapes of human breast and colorectal cancers. Science. 2007, 318: 1108-1113.CrossRefPubMed
6.
7.
Porter DA, Krop IE, Nasser S, Sgroi D, Kaelin CM, Marks JR, Riggins G, Polyak K: A SAGE (serial analysis of gene expression) view of breast tumor progression. Cancer Res. 2001, 61: 5697-5702.PubMed
8.
Ma XJ, Salunga R, Tuggle JT, Gaudet J, Enright E, McQuary P, Payette T, Pistone M, Stecker K, Zhang BM, Zhou YX, Varnholt H, Smith B, Gadd M, Chatfield E, Kessler J, Baer TM, Erlander MG, Sgroi DC: Gene expression profiles of human breast cancer progression. Proc Natl Acad Sci USA. 2003, 100: 5974-5979.CrossRefPubMedPubMedCentral
9.
Adeyinka A, Emberley E, Niu Y, Snell L, Murphy LC, Sowter H, Wykoff CC, Harris AL, Watson PH: Analysis of gene expression in ductal carcinoma in situ of the breast. Clin Cancer Res. 2002, 8: 3788-3795.PubMed
10.
Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K, Cobb MH: Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev. 2001, 22: 153-183.PubMed
11.
Lewis TS, Shapiro PS, Ahn NG: Signal transduction through MAP kinase cascades. Adv Cancer Res. 1998, 74: 49-139.CrossRefPubMed
12.
Paszek MJ, Zahir N, Johnson KR, Lakins JN, Rozenberg GI, Gefen A, Reinhart-King CA, Margulies SS, Dembo M, Boettiger D, Hammer DA, Weaver VM: Tensional homeostasis and the malignant phenotype. Cancer Cell. 2005, 8: 241-254.CrossRefPubMed
13.
Sivaraman VS, Wang H, Nuovo GJ, Malbon CC: Hyperexpression of mitogen-activated protein kinase in human breast cancer. J Clin Invest. 1997, 99: 1478-1483.CrossRefPubMedPubMedCentral
14.
Adeyinka A, Nui Y, Cherlet T, Snell L, Watson PH, Murphy LC: Activated mitogen-activated protein kinase expression during human breast tumorigenesis and breast cancer progression. Clin Cancer Res. 2002, 8: 1747-1753.PubMed
15.
Umemura S, Yoshida S, Ohta Y, Naito K, Osamura RY, Tokuda Y: Increased phosphorylation of Akt in triple-negative breast cancers. Cancer Sci. 2007, 98: 1889-1892.CrossRefPubMed
16.
English J, Pearson G, Wilsbacher J, Swantek J, Karandikar M, Xu S, Cobb MH: New insights into the control of MAP kinase pathways. Exp Cell Res. 1999, 253: 255-270.CrossRefPubMed
17.
Muthuswamy SK, Li D, Lelievre S, Bissell MJ, Brugge JS: ErbB2, but not ErbB1, reinitiates proliferation and induces luminal repopulation in epithelial acini. Nat Cell Biol. 2001, 3: 785-792.CrossRefPubMedPubMedCentral
18.
Debnath J, Walker SJ, Brugge JS: Akt activation disrupts mammary acinar architecture and enhances proliferation in an mTOR-dependent manner. J Cell Biol. 2003, 163: 315-326.CrossRefPubMedPubMedCentral
19.
Muthuswamy SK, Gilman M, Brugge JS: Controlled dimerization of ErbB receptors provides evidence for differential signaling by homo- and heterodimers. Mol Cell Biol. 1999, 19: 6845-6857.CrossRefPubMedPubMedCentral
20.
21.
Debnath J, Muthuswamy SK, Brugge JS: Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures. Methods. 2003, 30: 256-268.CrossRefPubMed
22.
23.
Mills KR, Reginato M, Debnath J, Queenan B, Brugge JS: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is required for induction of autophagy during lumen formation in vitro. Proc Natl Acad Sci USA. 2004, 101: 3438-3443.CrossRefPubMedPubMedCentral
24.
Debnath J, Mills KR, Collins NL, Reginato MJ, Muthuswamy SK, Brugge JS: The role of apoptosis in creating and maintaining luminal space within normal and oncogene-expressing mammary acini. Cell. 2002, 111: 29-40.CrossRefPubMed
25.
26.
Yanochko GM, Eckhart W: Type I insulin-like growth factor receptor over-expression induces proliferation and anti-apoptotic signaling in a three-dimensional culture model of breast epithelial cells. Breast Cancer Res. 2006, 8: R18-CrossRefPubMedPubMedCentral
27.
McCarthy SA, Samuels ML, Pritchard CA, Abraham JA, McMahon M: Rapid induction of heparin-binding epidermal growth factor/diphtheria toxin receptor expression by Raf and Ras oncogenes. Genes Dev. 1995, 9: 1953-1964.CrossRefPubMed
28.
Samuels ML, Weber MJ, Bishop JM, McMahon M: Conditional transformation of cells and rapid activation of the mitogen-activated protein kinase cascade by an estradiol-dependent human raf-1 protein kinase. Mol Cell Biol. 1993, 13: 6241-6252.CrossRefPubMedPubMedCentral
29.
McMahon M: Steroid receptor fusion proteins for conditional activation of Raf–MEK–ERK signaling pathway. Methods Enzymol. 2001, 332: 401-417.CrossRefPubMed
30.
Schulze A, Nicke B, Warne PH, Tomlinson S, Downward J: The transcriptional response to Raf activation is almost completely dependent on mitogen-activated protein kinase kinase activity and shows a major autocrine component. Mol Biol Cell. 2004, 15: 3450-3463.CrossRefPubMedPubMedCentral
31.
Schulze A, Lehmann K, Jefferies HB, McMahon M, Downward J: Analysis of the transcriptional program induced by Raf in epithelial cells. Genes Dev. 2001, 15: 981-994.CrossRefPubMedPubMedCentral
32.
Baselga J, Albanell J, Ruiz A, Lluch A, Gascon P, Guillem V, Gonzalez S, Sauleda S, Marimon I, Tabernero JM, Koehler MT, Rojo F: Phase II and tumor pharmacodynamic study of gefitinib in patients with advanced breast cancer. J Clin Oncol. 2005, 23: 5323-5333.CrossRefPubMed
33.
Marani M, Hancock D, Lopes R, Tenev T, Downward J, Lemoine NR: Role of Bim in the survival pathway induced by Raf in epithelial cells. Oncogene. 2004, 23: 2431-2441.CrossRefPubMed
34.
Jochum W, Passegue E, Wagner EF: AP-1 in mouse development and tumorigenesis. Oncogene. 2001, 20: 2401-2412.CrossRefPubMed
35.
Murphy LO, Smith S, Chen RH, Fingar DC, Blenis J: Molecular interpretation of ERK signal duration by immediate early gene products. Nat Cell Biol. 2002, 4: 556-564.PubMed
36.
Reginato MJ, Mills KR, Becker EB, Lynch DK, Bonni A, Muthuswamy SK, Brugge JS: Bim regulation of lumen formation in cultured mammary epithelial acini is targeted by oncogenes. Mol Cell Biol. 2005, 25: 4591-4601.CrossRefPubMedPubMedCentral
37.
Mailleux AA, Overholtzer M, Schmelzle T, Bouillet P, Strasser A, Brugge JS: BIM regulates apoptosis during mammary ductal morphogenesis, and its absence reveals alternative cell death mechanisms. Dev Cell. 2007, 12: 221-234.CrossRefPubMedPubMedCentral
38.
Liu H, Radisky DC, Wang F, Bissell MJ: Polarity and proliferation are controlled by distinct signaling pathways downstream of PI3-kinase in breast epithelial tumor cells. J Cell Biol. 2004, 164: 603-612.CrossRefPubMedPubMedCentral
39.
Van Keymeulen A, Wong K, Knight ZA, Govaerts C, Hahn KM, Shokat KM, Bourne HR: To stabilize neutrophil polarity, PIP3 and Cdc42 augment RhoA activity at the back as well as signals at the front. J Cell Biol. 2006, 174: 437-445.CrossRefPubMedPubMedCentral
40.
Musgrove EA, Davison EA, Ormandy CJ: Role of the CDK inhibitor p27 (Kip1) in mammary development and carcinogenesis: insights from knockout mice. J Mammary Gland Biol Neoplasia. 2004, 9: 55-66.CrossRefPubMed
41.
Hlobilkova A, Knillova J, Svachova M, Skypalova P, Krystof V, Kolar Z: Tumour suppressor PTEN regulates cell cycle and protein kinase B/Akt pathway in breast cancer cells. Anticancer Res. 2006, 26: 1015-1022.PubMed
42.
Mirza AM, Gysin S, Malek N, Nakayama K, Roberts JM, McMahon M: Cooperative regulation of the cell division cycle by the protein kinases RAF and AKT. Mol Cell Biol. 2004, 24: 10868-10881.CrossRefPubMedPubMedCentral
43.
Neve RM, Chin K, Fridlyand J, Yeh J, Baehner FL, Fevr T, Clark L, Bayani N, Coppe JP, Tong F, Speed T, Spellman PT, Devries S, Lapuk A, Wang NJ, Kuo WL, Stilwell JL, Pinkel D, Albertson DG, Waldman FM, McCormick F, Dickson RB, Johnson MD, Lippman M, Ethier S, Gazdar A, Gray JW: A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell. 2006, 10: 515-527.CrossRefPubMedPubMedCentral
44.
Solin LJ, Kurtz J, Fourquet A, Amalric R, Recht A, Bornstein BA, Kuske R, Taylor M, Barrett W, Fowble B, Haffty B, Schultz DJ, Yeh IT, McCormick B, McNeese M: Fifteen-year results of breast-conserving surgery and definitive breast irradiation for the treatment of ductal carcinoma in situ of the breast. J Clin Oncol. 1996, 14: 754-763.PubMed
45.
Solin LJ, Fourquet A, Vicini FA, Haffty B, Taylor M, McCormick B, McNeese M, Pierce LJ, Landmann C, Olivotto IA, Borger J, Kim J, de la Rochefordiere A, Schultz DJ: Mammographically detected ductal carcinoma in situ of the breast treated with breast-conserving surgery and definitive breast irradiation: long-term outcome and prognostic significance of patient age and margin status. Int J Radiat Oncol Biol Phys. 2001, 50: 991-1002.CrossRefPubMed
46.
Fisher B, Land S, Mamounas E, Dignam J, Fisher ER, Wolmark N: Prevention of invasive breast cancer in women with ductal carcinoma in situ: an update of the National Surgical Adjuvant Breast and Bowel Project experience. Semin Oncol. 2001, 28: 400-418.CrossRefPubMed
47.
Sebolt-Leopold JS, English JM: Mechanisms of drug inhibition of signalling molecules. Nature. 2006, 441: 457-462.CrossRefPubMed
48.
Dalby KN, Morrice N, Caudwell FB, Avruch J, Cohen P: Identification of regulatory phosphorylation sites in mitogen-activated protein kinase (MAPK)-activated protein kinase-1a/p90rsk that are inducible by MAPK. J Biol Chem. 1998, 273: 1496-1505.CrossRefPubMed
49.
50.
Chen RH, Abate C, Blenis J: Phosphorylation of the c-Fos transrepression domain by mitogen-activated protein kinase and 90-kDa ribosomal S6 kinase. Proc Natl Acad Sci USA. 1993, 90: 10952-10956.CrossRefPubMedPubMedCentral
51.
Rivera VM, Miranti CK, Misra RP, Ginty DD, Chen RH, Blenis J, Greenberg ME: A growth factor-induced kinase phosphorylates the serum response factor at a site that regulates its DNA-binding activity. Mol Cell Biol. 1993, 13: 6260-6273.CrossRefPubMedPubMedCentral
52.
Xing J, Ginty DD, Greenberg ME: Coupling of the RAS–MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase. Science. 1996, 273: 959-963.CrossRefPubMed
53.
Nakajima T, Fukamizu A, Takahashi J, Gage FH, Fisher T, Blenis J, Montminy MR: The signal-dependent coactivator CBP is a nuclear target for pp90RSK. Cell. 1996, 86: 465-474.CrossRefPubMed
54.
Roux PP, Ballif BA, Anjum R, Gygi SP, Blenis J: Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc Natl Acad Sci USA. 2004, 101: 13489-13494.CrossRefPubMedPubMedCentral
55.
Fang X, Yu S, Eder A, Mao M, Bast RC, Boyd D, Mills GB: Regulation of BAD phosphorylation at serine 112 by the Ras-mitogen-activated protein kinase pathway. Oncogene. 1999, 18: 6635-6640.CrossRefPubMed
56.
Cuevas BD, Abell AN, Witowsky JA, Yujiri T, Johnson NL, Kesavan K, Ware M, Jones PL, Weed SA, DeBiasi RL, Oka Y, Tyler KL, Johnson GL: MEKK1 regulates calpain-dependent proteolysis of focal adhesion proteins for rear-end detachment of migrating fibroblasts. EMBO J. 2003, 22: 3346-3355.CrossRefPubMedPubMedCentral
57.
Klemke RL, Cai S, Giannini AL, Gallagher PJ, de Lanerolle P, Cheresh DA: Regulation of cell motility by mitogen-activated protein kinase. J Cell Biol. 1997, 137: 481-492.CrossRefPubMedPubMedCentral
58.
Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE: High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004, 304: 554-CrossRefPubMed
59.
Luo J, Manning BD, Cantley LC: Targeting the PI3K–Akt pathway in human cancer: rationale and promise. Cancer Cell. 2003, 4: 257-262.CrossRefPubMed
60.
Depowski PL, Rosenthal SI, Ross JS: Loss of expression of the PTEN gene protein product is associated with poor outcome in breast cancer. Mod Pathol. 2001, 14: 672-676.CrossRefPubMed
61.
Iglesias PA, Devreotes PN: Navigating through models of chemotaxis. Curr Opin Cell Biol. 2008, 20: 35-40.CrossRefPubMed
62.
Wang F, Hansen RK, Radisky D, Yoneda T, Barcellos-Hoff MH, Petersen OW, Turley EA, Bissell MJ: Phenotypic reversion or death of cancer cells by altering signaling pathways in three-dimensional contexts. J Natl Cancer Inst. 2002, 94: 1494-1503.CrossRefPubMedPubMedCentral
Metadata
Title
PI-3 kinase activity is necessary for ERK1/2-induced disruption of mammary epithelial architecture
Authors
Gray W Pearson
Tony Hunter
Publication date
01-06-2009
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 3/2009
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr2259

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