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Open Access 01-12-2015 | Research article

Upregulation of EGFR signaling is correlated with tumor stroma remodeling and tumor recurrence in FGFR1-driven breast cancer

Authors: Xue B. Holdman, Thomas Welte, Kimal Rajapakshe, Adam Pond, Cristian Coarfa, Qianxing Mo, Shixia Huang, Susan G. Hilsenbeck, Dean P. Edwards, Xiang Zhang, Jeffrey M. Rosen

Published in: Breast Cancer Research | Issue 1/2015

Abstract

Introduction

Despite advances in early detection and adjuvant targeted therapies, breast cancer is still the second most common cause of cancer mortality among women. Tumor recurrence is one of the major contributors to breast cancer mortality. However, the mechanisms underlying this process are not completely understood. In this study, we investigated the mechanisms of tumor dormancy and recurrence in a preclinical mouse model of breast cancer.

Methods

To elucidate the mechanisms driving tumor recurrence, we employed a transplantable Wnt1/inducible fibroblast growth factor receptor (FGFR) 1 mouse mammary tumor model and utilized an FGFR specific inhibitor, BGJ398, to study the recurrence after treatment. Histological staining was performed to analyze the residual tumor cells and tumor stroma. Reverse phase protein array was performed to compare primary and recurrent tumors to investigate the molecular mechanisms leading to tumor recurrence.

Results

Treatment with BGJ398 resulted in rapid tumor regression, leaving a nonpalpable mass of dormant tumor cells organized into a luminal and basal epithelial layer similar to the normal mammary gland, but surrounded by dense stroma with markedly reduced levels of myeloid-derived tumor suppressor cells (MDSCs) and decreased tumor vasculature. Following cessation of treatment the tumors recurred over a period of 1 to 4 months. The recurrent tumors displayed dense stroma with increased collagen, tenascin-C expression, and MDSC infiltration. Activation of the epidermal growth factor receptor (EGFR) pathway was observed in recurrent tumors, and inhibition of EGFR with lapatinib in combination with BGJ398 resulted in a significant delay in tumor recurrence accompanied by reduced stroma, yet there was no difference observed in initial tumor regression between the groups treated with BGJ398 alone or in combination with lapatinib.

Conclusion

These studies have revealed a correlation between tumor recurrence and changes of stromal microenvironment accompanied by altered EGFR signaling.

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Aguirre-Ghiso JA. Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer. 2007;7(11):834–46. doi:10.1038/nrc2256.CrossRefPubMedPubMedCentral

Banys M, Hartkopf AD, Krawczyk N, Kaiser T, Meier-Stiegen F, Fehm T, et al. Dormancy in breast cancer. Breast Cancer. 2012;4:183–91. doi:10.2147/BCTT.S26431.PubMedPubMedCentral

Predina J, Eruslanov E, Judy B, Kapoor V, Cheng G, Wang LC, et al. Changes in the local tumor microenvironment in recurrent cancers may explain the failure of vaccines after surgery. Proc Natl Acad Sci U S A. 2013;110(5):E415–24. doi:10.1073/pnas.1211850110.CrossRefPubMed

Chien J, Kuang R, Landen C, Shridhar V. Platinum-sensitive recurrence in ovarian cancer: the role of tumor microenvironment. Front Oncol. 2013;3:251. doi:10.3389/fonc.2013.00251.CrossRefPubMedPubMedCentral

Boyd NF, Dite GS, Stone J, Gunasekara A, English DR, McCredie MR, et al. Heritability of mammographic density, a risk factor for breast cancer. N Engl J Med. 2002;347(12):886–94. doi:10.1056/NEJMoa013390.CrossRefPubMed

Ursin G, Hovanessian-Larsen L, Parisky YR, Pike MC, Wu AH. Greatly increased occurrence of breast cancers in areas of mammographically dense tissue. Breast Cancer Res. 2005;7(5):R605–8. doi:10.1186/bcr1260.CrossRefPubMedPubMedCentral

Maskarinec G, Woolcott CG, Kolonel LN. Mammographic density as a predictor of breast cancer outcome. Future Oncol. 2010;6(3):351–4. doi:10.2217/fon.10.3.CrossRefPubMedPubMedCentral

Jana SH, Jha BM, Patel C, Jana D, Agarwal A. CD10-a new prognostic stromal marker in breast carcinoma, its utility, limitations and role in breast cancer pathogenesis. Indian J Pathol Microbiol. 2014;57(4):530–6. doi:10.4103/0377-4929.142639.CrossRefPubMed

Auvinen P, Rilla K, Tumelius R, Tammi M, Sironen R, Soini Y, et al. Hyaluronan synthases (HAS1-3) in stromal and malignant cells correlate with breast cancer grade and predict patient survival. Breast Cancer Res Treat. 2014;143(2):277–86. doi:10.1007/s10549-013-2804-7.CrossRefPubMed

10.

Ahn S, Cho J, Sung J, Lee JE, Nam SJ, Kim KM, et al. The prognostic significance of tumor-associated stroma in invasive breast carcinoma. Tumour Biol. 2012;33(5):1573–80. doi:10.1007/s13277-012-0411-6.CrossRefPubMed

11.

Moody SE, Perez D, Pan TC, Sarkisian CJ, Portocarrero CP, Sterner CJ, et al. The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell. 2005;8(3):197–209. doi:10.1016/j.ccr.2005.07.009.CrossRefPubMed

12.

Abravanel DL, Belka GK, Pan TC, Pant DK, Collins MA, Sterner CJ, et al. Notch promotes recurrence of dormant tumor cells following HER2/neu-targeted therapy. J Clin Invest. 2015;125(6):2484–96. doi:10.1172/JCI74883.CrossRefPubMedPubMedCentral

13.

Haugsten EM, Wiedlocha A, Olsnes S, Wesche J. Roles of fibroblast growth factor receptors in carcinogenesis. Mol Cancer Res. 2010;8(11):1439–52. doi:10.1158/1541-7786.MCR-10-0168.CrossRefPubMed

14.

Yang F, Gao Y, Geng J, Qu D, Han Q, Qi J, et al. Elevated expression of SOX2 and FGFR1 in correlation with poor prognosis in patients with small cell lung cancer. Int J Clin Exp Pathol. 2013;6(12):2846–54.PubMedPubMedCentral

15.

Zhang H, Hylander BL, LeVea C, Repasky EA, Straubinger RM, Adjei AA, et al. Enhanced FGFR signalling predisposes pancreatic cancer to the effect of a potent FGFR inhibitor in preclinical models. Br J Cancer. 2014;110(2):320–9. doi:10.1038/bjc.2013.754.CrossRefPubMed

16.

Gru AA, Allred DC. FGFR1 amplification and the progression of non-invasive to invasive breast cancer. Breast Cancer Res. 2012;14(6):116. doi:10.1186/bcr3340.CrossRefPubMedPubMedCentral

17.

Shackleford GM, Willert K, Wang J, Varmus HE. The Wnt-1 proto-oncogene induces changes in morphology, gene expression, and growth factor responsiveness in PC12 cells. Neuron. 1993;11(5):865–75.CrossRefPubMed

18.

Lee FS, Lane TF, Kuo A, Shackleford GM, Leder P. Insertional mutagenesis identifies a member of the Wnt gene family as a candidate oncogene in the mammary epithelium of int-2/Fgf-3 transgenic mice. Proc Natl Acad Sci U S A. 1995;92(6):2268–72.CrossRefPubMedPubMedCentral

19.

Theodorou V, Kimm MA, Boer M, Wessels L, Theelen W, Jonkers J, et al. MMTV insertional mutagenesis identifies genes, gene families and pathways involved in mammary cancer. Nat Genet. 2007;39(6):759–69. doi:10.1038/ng2034.CrossRefPubMed

20.

Pond AC, Herschkowitz JI, Schwertfeger KL, Welm B, Zhang Y, York B, et al. Fibroblast growth factor receptor signaling dramatically accelerates tumorigenesis and enhances oncoprotein translation in the mouse mammary tumor virus-Wnt-1 mouse model of breast cancer. Cancer Res. 2010;70(12):4868–79. doi:10.1158/0008-5472.CAN-09-4404.CrossRefPubMedPubMedCentral

21.

Turner N, Pearson A, Sharpe R, Lambros M, Geyer F, Lopez-Garcia MA, et al. FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res. 2010;70(5):2085–94. doi:10.1158/0008-5472.CAN-09-3746.CrossRefPubMedPubMedCentral

22.

Guagnano V, Furet P, Spanka C, Bordas V, Le Douget M, Stamm C, et al. Discovery of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamin o]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase. J Med Chem. 2011;54(20):7066–83. doi:10.1021/jm2006222.CrossRefPubMed

23.

Grimm SL, Contreras A, Barcellos-Hoff MH, Rosen JM. Cell cycle defects contribute to a block in hormone-induced mammary gland proliferation in CCAAT/enhancer-binding protein (C/EBPbeta)-null mice. J Biol Chem. 2005;280(43):36301–9. doi:10.1074/jbc.M508167200.CrossRefPubMed

24.

Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9(7):671–5.CrossRefPubMed

25.

Dong S, Jia C, Zhang S, Fan G, Li Y, Shan P, et al. The REGgamma proteasome regulates hepatic lipid metabolism through inhibition of autophagy. Cell Metab. 2013;18(3):380–91. doi:10.1016/j.cmet.2013.08.012.CrossRefPubMed

26.

Grubb RL, Deng J, Pinto PA, Mohler JL, Chinnaiyan A, Rubin M, et al. Pathway biomarker profiling of localized and metastatic human prostate cancer reveal metastatic and prognostic signatures. J Proteome Res. 2009;8(6):3044–54. doi:10.1021/pr8009337.CrossRefPubMedPubMedCentral

27.

Huang S, Li Y, Chen Y, Podsypanina K, Chamorro M, Olshen AB, et al. Changes in gene expression during the development of mammary tumors in MMTV-Wnt-1 transgenic mice. Genome Biol. 2005;6(10):R84. doi:10.1186/gb-2005-6-10-r84.CrossRefPubMedPubMedCentral

28.

Welm BE, Freeman KW, Chen M, Contreras A, Spencer DM, Rosen JM. Inducible dimerization of FGFR1: development of a mouse model to analyze progressive transformation of the mammary gland. J Cell Biol. 2002;157(4):703–14. doi:10.1083/jcb.200107119.CrossRefPubMedPubMedCentral

29.

Xian W, Schwertfeger KL, Rosen JM. Distinct roles of fibroblast growth factor receptor 1 and 2 in regulating cell survival and epithelial-mesenchymal transition. Mol Endocrinol. 2007;21(4):987–1000. doi:10.1210/me.2006-0518.CrossRefPubMed

30.

Wang SH, Lin SY. Tumor dormancy: potential therapeutic target in tumor recurrence and metastasis prevention. Exp Hematol Oncol. 2013;2(1):29. doi:10.1186/2162-3619-2-29.CrossRefPubMedPubMedCentral

31.

Weinstein IB. Cancer. Addiction to oncogenes—the Achilles heal of cancer. Science. 2002;297(5578):63–4. doi:10.1126/science.1073096.CrossRefPubMed

32.

Pandey PR, Saidou J, Watabe K. Role of myoepithelial cells in breast tumor progression. Front Biosci. 2010;15:226–36.CrossRef

33.

Kleffel S, Schatton T. Tumor dormancy and cancer stem cells: two sides of the same coin? Adv Exp Med Biol. 2013;734:145–79. doi:10.1007/978-1-4614-1445-2_8.CrossRefPubMed

34.

Hasebe T, Sasaki S, Imoto S, Mukai K, Yokose T, Ochiai A. Prognostic significance of fibrotic focus in invasive ductal carcinoma of the breast: a prospective observational study. Modern Path. 2002;15(5):502–16. doi:10.1038/modpathol.3880555.CrossRef

35.

Van den Eynden GG, Smid M, Van Laere SJ, Colpaert CG, Van der Auwera I, Bich TX, et al. Gene expression profiles associated with the presence of a fibrotic focus and the growth pattern in lymph node-negative breast cancer. Clin Cancer Res. 2008;14(10):2944–52. doi:10.1158/1078-0432.CCR-07-4397.CrossRefPubMed

36.

Raviraj V, Zhang H, Chien HY, Cole L, Thompson EW, Soon L. Dormant but migratory tumour cells in desmoplastic stroma of invasive ductal carcinomas. Clin Exp Metastasis. 2012;29(3):273–92. doi:10.1007/s10585-011-9450-4.CrossRefPubMed

37.

Jensen BV, Johansen JS, Skovsgaard T, Brandt J, Teisner B. Extracellular matrix building marked by the N-terminal propeptide of procollagen type I reflect aggressiveness of recurrent breast cancer. Int J Cancer. 2002;98(4):582–9.CrossRefPubMed

38.

Barkan D, El Touny LH, Michalowski AM, Smith JA, Chu I, Davis AS, et al. Metastatic growth from dormant cells induced by a col-I-enriched fibrotic environment. Cancer Res. 2010;70(14):5706–16. doi:10.1158/0008-5472.CAN-09-2356.CrossRefPubMedPubMedCentral

39.

Hu M, Yao J, Carroll DK, Weremowicz S, Chen H, Carrasco D, et al. Regulation of in situ to invasive breast carcinoma transition. Cancer Cell. 2008;13(5):394–406. doi:10.1016/j.ccr.2008.03.007.CrossRefPubMedPubMedCentral

40.

Markowitz J, Wesolowski R, Papenfuss T, Brooks TR, Carson 3rd WE. Myeloid-derived suppressor cells in breast cancer. Breast Cancer Res Treat. 2013;140(1):13–21. doi:10.1007/s10549-013-2618-7.CrossRefPubMedPubMedCentral

41.

Midwood KS, Hussenet T, Langlois B, Orend G. Advances in tenascin-C biology. Cell Mol Life Sci. 2011;68(19):3175–99. doi:10.1007/s00018-011-0783-6.CrossRefPubMedPubMedCentral

42.

Swindle CS, Tran KT, Johnson TD, Banerjee P, Mayes AM, Griffith L, et al. Epidermal growth factor (EGF)-like repeats of human tenascin-C as ligands for EGF receptor. J Cell Biol. 2001;154(2):459–68.CrossRefPubMedPubMedCentral

43.

Sternlicht MD, Sunnarborg SW, Kouros-Mehr H, Yu Y, Lee DC, Werb Z. Mammary ductal morphogenesis requires paracrine activation of stromal EGFR via ADAM17-dependent shedding of epithelial amphiregulin. Development. 2005;132(17):3923–33. doi:10.1242/dev.01966.CrossRefPubMedPubMedCentral

44.

Bade LK, Goldberg JE, Dehut HA, Hall MK, Schwertfeger KL. Mammary tumorigenesis induced by fibroblast growth factor receptor 1 requires activation of the epidermal growth factor receptor. J Cell Sci. 2011;124(Pt 18):3106–17. doi:10.1242/jcs.082651.CrossRefPubMedPubMedCentral

45.

Azuma K, Kawahara A, Sonoda K, Nakashima K, Tashiro K, Watari K, et al. FGFR1 activation is an escape mechanism in human lung cancer cells resistant to afatinib, a pan-EGFR family kinase inhibitor. Oncotarget. 2014;5(15):5908–19.CrossRefPubMedPubMedCentral

46.

Issa A, Gill JW, Heideman MR, Sahin O, Wiemann S, Dey JH, et al. Combinatorial targeting of FGF and ErbB receptors blocks growth and metastatic spread of breast cancer models. Breast Cancer Res. 2013;15(1):R8. doi:10.1186/bcr3379.CrossRefPubMedPubMedCentral

47.

McCarthy NJ, Swain SM. Update on adjuvant chemotherapy for early breast cancer. Oncology (Williston Park). 2000;14(9):1267–80. discussion 1280–4, 1287–8.

48.

Papadimitriou K, Ardavanis A, Kountourakis P. Neoadjuvant therapy for locally advanced breast cancer: focus on chemotherapy and biological targeted treatments’ armamentarium. J Thorac Dis. 2010;2(3):160–70. doi:10.3978/j.issn.2072-1439.2010.02.03.8.PubMed

Title: Upregulation of EGFR signaling is correlated with tumor stroma remodeling and tumor recurrence in FGFR1-driven breast cancer
Authors: Xue B. Holdman
Thomas Welte
Kimal Rajapakshe
Adam Pond
Cristian Coarfa
Qianxing Mo
Shixia Huang
Susan G. Hilsenbeck
Dean P. Edwards
Xiang Zhang
Jeffrey M. Rosen
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: Breast Cancer Research / Issue 1/2015
Electronic ISSN: 1465-542X
DOI: https://doi.org/10.1186/s13058-015-0649-1

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Abstract

Introduction

Methods

Results

Conclusion

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