Top

Published in:

01-09-2011 | Preclinical study

Ras-related protein 1 and the insulin-like growth factor type I receptor are associated with risk of progression in patients diagnosed with carcinoma in situ

Authors: Dana K. Furstenau, Nandita Mitra, Fei Wan, Robert Lewis, Michael D. Feldman, Douglas L. Fraker, Marina A. Guvakova

Published in: Breast Cancer Research and Treatment | Issue 2/2011

Abstract

Currently, there are no applied molecular markers to aid in predicting risk of carcinoma in situ (CIS) progression to invasive cancer, and therefore, all women diagnosed with CIS undergo surgery. Standard assessment of protein expression in fixed tissue by immunohistochemistry (IHC) is not quantitative and hence is not well suited for measuring biomarkers. In this study, we developed an original analytical method for IHC quantification. Using our novel image-based uniplex (IBU) method, quantitative protein profiling was performed on 90 samples of the breast (17 histologically normal tissues, 16 benign lesions, 15 CIS, and 42 invasive carcinomas). Differences between groups were assessed using analysis of variance (ANOVA) and mixed effects models. Measuring protein expression on a continuous scale revealed a significant increase in Ras-related protein 1 (Rap1) and the insulin-like growth factor type I receptor (IGF-IR) in conjunction with the presence of cancer invasion. Women with invasive cancers were four times more likely to have increased levels of Rap1 [odds ratio (OR) = 3.91; P = 0.0002] and IGF-IR (OR = 4.33; P < 0.0001) than women with non-invasive lesions. Furthermore, expression of both proteins was also increased significantly in CIS adjacent to invasive tumors compared with non-cancerous tissue. These novel findings of a significant up-regulation of Rap1 and IGF-IR in CIS progressing to invasive cancers warrant further investigation of Rap1 and IGF-IR together as a dual biomarker to aid in predicting risk of progression and ultimately providing non-surgical treatment options to those at lower risk.

Available only for authorised users

Allegra CJ, Aberle DR, Ganschow P, Hahn SM, Lee CN, Millon-Underwood S, Pike MC, Reed SD, Saftlas AF, Scarvalone SA, Schwartz AM, Slomski C, Yothers G, Zon R (2010) National Institutes of Health State-of-the-Science Conference statement: diagnosis and management of ductal carcinoma in situ September 22–24, 2009. J Natl Cancer Inst 102:161–169PubMedCrossRef

Kerlikowske K, Molinaro AM, Gauthier ML, Berman HK, Waldman F, Bennington J, Sanchez H, Jimenez C, Stewart K, Chew K, Ljung BM, Tlsty TD (2010) Biomarker expression and risk of subsequent tumors after initial ductal carcinoma in situ diagnosis. J Natl Cancer Inst 102:627–637PubMedCrossRef

Kuerer HM, Albarracin CT, Yang WT, Cardiff RD, Brewster AM, Symmans WF, Hylton NM, Middleton LP, Krishnamurthy S, Perkins GH, Babiera G, Edgerton ME, Czerniecki BJ, Arun BK, Hortobagyi GN (2009) Ductal carcinoma in situ: state of the science and roadmap to advance the field. J Clin Oncol 27:279–288PubMedCrossRef

Hoorntje LE, Schipper ME, Peeters PH, Bellot F, Storm RK, Borel RI (2003) The finding of invasive cancer after a preoperative diagnosis of ductal carcinoma-in situ: causes of ductal carcinoma-in situ underestimates with stereotactic 14-gauge needle biopsy. Ann Surg Oncol 10:748–753PubMedCrossRef

Huo L, Sneige N, Hunt KK, Albarracin CT, Lopez A, Resetkova E (2006) Predictors of invasion in patients with core-needle biopsy-diagnosed ductal carcinoma in situ and recommendations for a selective approach to sentinel lymph node biopsy in ductal carcinoma in situ. Cancer 107:1760–1768PubMedCrossRef

Meijnen P, Oldenburg HS, Loo CE, Nieweg OE, Peterse JL, Rutgers EJ (2007) Risk of invasion and axillary lymph node metastasis in ductal carcinoma in situ diagnosed by core-needle biopsy. Br J Surg 94:952–956PubMedCrossRef

Renshaw AA (2002) Predicting invasion in the excision specimen from breast core needle biopsy specimens with only ductal carcinoma in situ. Arch Pathol Lab Med 126:39–41PubMed

Roses RE, Paulson EC, Sharma A, Schueller JE, Nisenbaum H, Weinstein S, Fox KR, Zhang PJ, Czerniecki BJ (2009) HER-2/neu overexpression as a predictor for the transition from in situ to invasive breast cancer. Cancer Epidemiol Biomarkers Prev 18:1386–1389PubMedCrossRef

Kohn EC, Francis EA, Liotta LA, Schiffmann E (1990) Heterogeneity of the motility responses in malignant tumor cells: a biological basis for the diversity and homing of metastatic cells. Int J Cancer 46:287–292PubMedCrossRef

10.

Doerr ME, Jones JI (1996) The roles of integrins and extracellular matrix proteins in the insulin-like growth factor I-stimulated chemotaxis of human breast cancer cells. J Biol Chem 271:2443–2447PubMedCrossRef

11.

Guvakova MA, Surmacz E (1997) Overexpressed IGF-I receptors reduce estrogen growth requirements, enhance survival, and promote E-cadherin-mediated cell–cell adhesion in human breast cancer cells. Exp Cell Res 231:149–162PubMedCrossRef

12.

Shakibaei M, John T, De Souza P, Rahmanzadeh R, Merker HJ (1999) Signal transduction by beta1 integrin receptors in human chondrocytes in vitro: collaboration with the insulin-like growth factor-I receptor. Biochem J 342(Pt 3):615–623PubMedCrossRef

13.

Vuori K, Ruoslahti E (1994) Association of insulin receptor substrate-1 with integrins. Science 266:1576–1578PubMedCrossRef

14.

Lopez T, Hanahan D (2002) Elevated levels of IGF-1 receptor convey invasive and metastatic capability in a mouse model of pancreatic islet tumorigenesis. Cancer Cell 1:339–353PubMedCrossRef

15.

All-Ericsson C, Girnita L, Seregard S, Bartolazzi A, Jager MJ, Larsson O (2002) Insulin-like growth factor-1 receptor in uveal melanoma: a predictor for metastatic disease and a potential therapeutic target. Invest Ophthalmol Vis Sci 43:1–8PubMed

16.

Brodt P, Samani A, Navab R (2000) Inhibition of the type I insulin-like growth factor receptor expression and signaling: novel strategies for antimetastatic therapy. Biochem Pharmacol 60:1101–1107PubMedCrossRef

17.

Jackson JG, Zhang X, Yoneda T, Yee D (2001) Regulation of breast cancer cell motility by insulin receptor substrate-2 (IRS-2) in metastatic variants of human breast cancer cell lines. Oncogene 20:7318–7325PubMedCrossRef

18.

Nishizuka I, Ishikawa T, Hamaguchi Y, Kamiyama M, Ichikawa Y, Kadota K, Miki R, Tomaru Y, Mizuno Y, Tominaga N, Yano R, Goto H, Nitanda H, Togo S, Okazaki Y, Hayashizaki Y, Shimada H (2002) Analysis of gene expression involved in brain metastasis from breast cancer using cDNA microarray. Breast Cancer 9:26–32PubMedCrossRef

19.

Happerfield LC, Miles DW, Barnes DM, Thomsen LL, Smith P, Hanby A (1997) The localization of the insulin-like growth factor receptor 1 (IGFR-1) in benign and malignant breast tissue. J Pathol 183:412–417PubMedCrossRef

20.

Resnik JL, Reichart DB, Huey K, Webster NJ, Seely BL (1998) Elevated insulin-like growth factor I receptor autophosphorylation and kinase activity in human breast cancer. Cancer Res 58:1159–1164PubMed

21.

Shimizu C, Hasegawa T, Tani Y, Takahashi F, Takeuchi M, Watanabe T, Ando M, Katsumata N, Fujiwara Y (2004) Expression of insulin-like growth factor 1 receptor in primary breast cancer: immunohistochemical analysis. Hum Pathol 35:1537–1542PubMedCrossRef

22.

Nielsen TO, Andrews HN, Cheang M, Kucab JE, Hsu FD, Ragaz J, Gilks CB, Makretsov N, Bajdik CD, Brookes C, Neckers LM, Evdokimova V, Huntsman DG, Dunn SE (2004) Expression of the insulin-like growth factor I receptor and urokinase plasminogen activator in breast cancer is associated with poor survival: potential for intervention with 17-allylamino geldanamycin. Cancer Res 64:286–291PubMedCrossRef

23.

van Golen KL (2003) Inflammatory breast cancer: relationship between growth factor signaling and motility in aggressive cancers. Breast Cancer Res 5:174–179PubMedCrossRef

24.

Chitnis MM, Yuen JS, Protheroe AS, Pollak M, Macaulay VM (2008) The type 1 insulin-like growth factor receptor pathway. Clin Cancer Res 14:6364–6370PubMedCrossRef

25.

Romano D, Pertuit M, Rasolonjanahary R, Barnier JV, Magalon K, Enjalbert A, Gerard C (2006) Regulation of the RAP1/RAF-1/extracellularly regulated kinase-1/2 cascade and prolactin release by the phosphoinositide 3-kinase/AKT pathway in pituitary cells. Endocrinology 147:6036–6045PubMedCrossRef

26.

Guvakova MA, Lee WSY (2009) Tuberin and hamartin in moving breast cancer cells expression localization and function. In: Abreu T, Silva G (eds) Cell movement new research trends. Nova Science Publishers, New York, pp 187–207

27.

Paganini S, Guidetti GF, Catricala S, Trionfini P, Panelli S, Balduini C, Torti M (2006) Identification and biochemical characterization of Rap2C, a new member of the Rap family of small GTP-binding proteins. Biochimie 88:285–295PubMedCrossRef

28.

Bos JL, de Rooij J, Reedquist KA (2001) Rap1 signalling: adhering to new models. Nat Rev Mol Cell Biol 2:369–377PubMedCrossRef

29.

Bokoch GM (1993) Biology of the Rap proteins, members of the ras superfamily of GTP-binding proteins. Biochem J 289(Pt 1):17–24PubMed

30.

Bos JL (2005) Linking Rap to cell adhesion. Curr Opin Cell Biol 17:123–128PubMedCrossRef

31.

Caron E (2003) Cellular functions of the Rap1 GTP-binding protein: a pattern emerges. J Cell Sci 116:435–440PubMedCrossRef

32.

Hattori M, Minato N (2003) Rap1 GTPase: functions, regulation, and malignancy. J Biochem 134:479–484PubMedCrossRef

33.

Frische EW, Zwartkruis FJ (2010) Rap1, a mercenary among the Ras-like GTPases. Dev Biol 340:1–9PubMedCrossRef

34.

Gutmann DH, Saporito-Irwin S, De Clue JE, Wienecke R, Guha A (1997) Alterations in the rap1 signaling pathway are common in human gliomas. Oncogene 15:1611–1616PubMedCrossRef

35.

Jiang WG, Sampson J, Martin TA, Lee-Jones L, Watkins G, Douglas-Jones A, Mokbel K, Mansel RE (2005) Tuberin and hamartin are aberrantly expressed and linked to clinical outcome in human breast cancer: the role of promoter methylation of TSC genes. Eur J Cancer 41:1628–1636PubMedCrossRef

36.

Zhang L, Chenwei L, Mahmood R, van Golen K, Greenson J, Li G, D’Silva NJ, Li X, Burant CF, Logsdon CD, Simeone DM (2006) Identification of a putative tumor suppressor gene Rap1GAP in pancreatic cancer. Cancer Res 66:898–906PubMedCrossRef

37.

Nellore A, Paziana K, Ma C, Tsygankova OM, Wang Y, Puttaswamy K, Iqbal AU, Franks SR, Lv Y, Troxel AB, Feldman MD, Meinkoth JL, Brose MS (2009) Loss of Rap1GAP in papillary thyroid cancer. J Clin Endocrinol Metab 94:1026–1032PubMedCrossRef

38.

Yajnik V, Paulding C, Sordella R, McClatchey AI, Saito M, Wahrer DC, Reynolds P, Bell DW, Lake R, Van, den Heuvel S, Settleman J, Haber DA (2003) DOCK4, a GTPase activator, is disrupted during tumorigenesis. Cell 112:673–684PubMedCrossRef

39.

Hirata T, Nagai H, Koizumi K, Okino K, Harada A, Onda M, Nagahata T, Mikami I, Hirai K, Haraguchi S, Jin E, Kawanami O, Shimizu K, Emi M (2004) Amplification, up-regulation and over-expression of C3G (CRK SH3 domain-binding guanine nucleotide-releasing factor) in non-small cell lung cancers. J Hum Genet 49(6):290–295PubMedCrossRef

40.

Kinashi T, Katagiri K (2004) Regulation of lymphocyte adhesion and migration by the small GTPase Rap1 and its effector molecule, RAPL. Immunol Lett 93:1–5PubMedCrossRef

41.

Fujita H, Fukuhara S, Sakurai A, Yamagishi A, Kamioka Y, Nakaoka Y, Masuda M, Mochizuki N (2005) Local activation of Rap1 contributes to directional vascular endothelial cell migration accompanied by extension of microtubules on which RAPL, a Rap1-associating molecule, localizes. J Biol Chem 280:5022–5031PubMedCrossRef

42.

Takahashi M, Rikitake Y, Nagamatsu Y, Hara T, Ikeda W, Hirata K, Takai Y (2008) Sequential activation of Rap1 and Rac1 small G proteins by PDGF locally at leading edges of NIH3T3 cells. Genes Cells 13:549–569PubMedCrossRef

43.

Itoh M, Nelson CM, Myers CA, Bissell MJ (2007) Rap1 integrates tissue polarity, lumen formation, and tumorigenic potential in human breast epithelial cells. Cancer Res 67:4759–4766PubMedCrossRef

44.

McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2006) Reporting recommendations for tumor marker prognostic studies (remark). Exp Oncol 28:99–105PubMed

45.

Becker KF, Schott C, Hipp S, Metzger V, Porschewski P, Beck R, Nahrig J, Becker I, Hofler H (2007) Quantitative protein analysis from formalin-fixed tissues: implications for translational clinical research and nanoscale molecular diagnosis. J Pathol 211:370–378PubMedCrossRef

46.

McCarty KS Jr, Szabo E, Flowers JL, Cox EB, Leight GS, Miller L, Konrath J, Soper JT, Budwit DA, Creasman WT (1986) Use of a monoclonal anti-estrogen receptor antibody in the immunohistochemical evaluation of human tumors. Cancer Res 46:4244s–4248sPubMed

47.

Cregger M, Berger AJ, Rimm DL (2006) Immunohistochemistry and quantitative analysis of protein expression. Arch Pathol Lab Med 130:1026–1030PubMed

48.

Guvakova MA (2007) Insulin-like growth factors control cell migration in health and disease. Int J Biochem Cell Biol 39:890–909PubMedCrossRef

49.

Zha J, Lackner MR (2010) Targeting the insulin-like growth factor receptor-1R pathway for cancer therapy. Clin Cancer Res 16:2512–2517PubMedCrossRef

50.

Polyak K (2002) Molecular alterations in ductal carcinoma in situ of the breast. Curr Opin Oncol 14:92–96PubMedCrossRef

51.

Wiechmann L, Kuerer HM (2008) The molecular journey from ductal carcinoma in situ to invasive breast cancer. Cancer 112:2130–2142PubMedCrossRef

52.

Lann D, LeRoith D (2008) The role of endocrine insulin-like growth factor-I and insulin in breast cancer. J Mammary Gland Biol Neoplasia 13:371–379PubMedCrossRef

53.

Schnarr B, Strunz K, Ohsam J, Benner A, Wacker J, Mayer D (2000) Down-regulation of insulin-like growth factor-I receptor and insulin receptor substrate-1 expression in advanced human breast cancer. Int J Cancer 89:506–513PubMedCrossRef

54.

Peyrat JP, Bonneterre J, Beuscart R, Djiane J, Demaille A (1988) Insulin-like growth factor 1 receptors in human breast cancer and their relation to estradiol and progesterone receptors. Cancer Res 48:6429–6433PubMed

55.

Jones RA, Campbell CI, Gunther EJ, Chodosh LA, Petrik JJ, Khokha R, Moorehead RA (2007) Transgenic overexpression of IGF-IR disrupts mammary ductal morphogenesis and induces tumor formation. Oncogene 26:1636–1644PubMedCrossRef

56.

Kucab JE, Dunn SE (2003) Role of IGF-1R in mediating breast cancer invasion and metastasis. Breast Dis 17:41–47PubMed

57.

Waldman FM, De Vries S, Chew KL, Moore DH, Kerlikowske K, Ljung BM (2000) Chromosomal alterations in ductal carcinomas in situ and their in situ recurrences. J Natl Cancer Inst 92:313–320PubMedCrossRef

58.

Miller BS, Yee D (2005) Type I insulin-like growth factor receptor as a therapeutic target in cancer. Cancer Res 65:10123–10127PubMedCrossRef

59.

Yee D (2007) Targeting insulin-like growth factor pathways. Br J Cancer 96(Supp l):7–10

60.

Rodon J, De Santos V, Ferry RJ Jr, Kurzrock R (2008) Early drug development of inhibitors of the insulin-like growth factor-I receptor pathway: lessons from the first clinical trials. Mol Cancer Ther 7:2575–2588PubMedCrossRef

61.

Lobell RB, Liu D, Buser CA, Davide JP, De Puy E, Hamilton K, Koblan KS, Lee Y, Mosser S, Motzel SL, Abbruzzese JL, Fuchs CS, Rowinsky EK, Rubin EH, Sharma S, Deutsch PJ, Mazina KE, Morrison BW, Wildonger L, Yao SL, Kohl NE (2002) Preclinical and clinical pharmacodynamic assessment of L-778, 123, a dual inhibitor of farnesyl:protein transferase and geranylgeranyl:protein transferase type-I. Mol Cancer Ther 1:747–758PubMed

62.

Sun J, Ohkanda J, Coppola D, Yin H, Kothare M, Busciglio B, Hamilton AD, Sebti SM (2003) Geranylgeranyltransferase I inhibitor GGTI-2154 induces breast carcinoma apoptosis and tumor regression in H-Ras transgenic mice. Cancer Res 63:8922–8929PubMed

Title: Ras-related protein 1 and the insulin-like growth factor type I receptor are associated with risk of progression in patients diagnosed with carcinoma in situ
Authors: Dana K. Furstenau
Nandita Mitra
Fei Wan
Robert Lewis
Michael D. Feldman
Douglas L. Fraker
Marina A. Guvakova
Publication date: 01-09-2011
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 2/2011
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-010-1227-y

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2011

Obesity and breast cancer survival in ethnically diverse postmenopausal women: the Multiethnic Cohort Study

Surgery of the primary tumor does not improve survival in stage IV breast cancer

Adipose levels of polybrominated diphenyl ethers and risk of breast cancer

Cancer risk in Jewish BRCA1 and BRCA2 mutation carriers: Effects of oral contraceptive use and parental origin of mutation

Nuclear co-localization and functional interaction of COX-2 and HIF-1α characterize bone metastasis of human breast carcinoma

Biologic markers determine both the risk and the timing of recurrence in breast cancer

Keynote webinar | Spotlight on antibody–drug conjugates in cancer