Advertisement

Breast Cancer Research and Treatment

, Volume 123, Issue 2, pp 397–404 | Cite as

Analysis of stromal signatures in the tumor microenvironment of ductal carcinoma in situ

  • M. Sharma
  • A. H. Beck
  • J. A. Webster
  • I. Espinosa
  • K. Montgomery
  • S. Varma
  • M. van de Rijn
  • K. C. Jensen
  • R. B. WestEmail author
Preclinical study

Abstract

Recent advances in the study of the tumor microenvironment have revealed significant interaction between tumor cells and their surrounding stroma in model systems. We have previously shown that two distinct stromal signatures derived from a macrophage (CSF1) response and a fibroblastic (DTF-like) response are present in subsets of invasive breast cancers and show a correlation with clinical outcome [1, 2, 3]. In the present study we explore whether these signatures also exist in the stroma of ductal carcinoma in situ (DCIS). We studied the signatures by both gene expression profile analysis of a publically available data set of DCIS and by immunohistochemistry (IHC) on a tissue microarray of DCIS and invasive breast cancer cases. Both the gene expression and immunohistochemical data show that the macrophage response and fibroblast expression signatures are present in the stroma of subsets of DCIS cases. The incidence of the stromal signatures in DCIS is similar to the incidence in invasive breast cancer that we have previously reported. We also find that the macrophage response signature is associated with higher grade DCIS and cases which are ER and PR negative, whereas the fibroblast signature was not associated with any clinicopathologic features in DCIS. A comparison of 115 matched cases of DCIS and invasive breast cancer found a correlation between the type of stromal response in DCIS and invasive ductal carcinoma (IDC) within the same patient for both the macrophage response and the fibroblast stromal signatures (P = 0.03 and 0.08, respectively). This study is a first characterization of these signatures in DCIS. These signatures have significant clinicopathologic associations and tend to be conserved as the tumor progresses from DCIS to invasive breast cancer.

Keywords

Ductal carcinoma in situ Tumor microenvironment Cancer stroma Fibroblast Macrophage 

Notes

Acknowledgments

Supported in part by research grants from the California Breast Cancer Research Program 15NB-0156 and the National Cancer Institute R01 CA129927.

References

  1. 1.
    Beck AH, Espinosa I, Edris B, Li R, Montgomery K, Zhu S, Varma S, Marinelli RJ, van de Rijn M, West RB (2009) The macrophage colony-stimulating factor 1 response signature in breast carcinoma. Clin Cancer Res 15(3):778–787CrossRefPubMedGoogle Scholar
  2. 2.
    Beck AH, Espinosa I, Gilks CB, van de Rijn M, West RB (2008) The fibromatosis signature defines a robust stromal response in breast carcinoma. Lab Invest 88(6):591–601CrossRefPubMedGoogle Scholar
  3. 3.
    West RB, Nuyten DS, Subramanian S, Nielsen TO, Corless CL, Rubin BP, Montgomery K, Zhu S, Patel R, Hernandez-Boussard T, Goldblum JR, Brown PO, van de Vijver M, van de Rijn M (2005) Determination of stromal signatures in breast carcinoma. PLoS Biol 3(6):e187CrossRefPubMedGoogle Scholar
  4. 4.
    Ernster VL, Barclay J, Kerlikowske K, Grady D, Henderson C (1996) Incidence of and treatment for ductal carcinoma in situ of the breast. JAMA 275(12):913–918CrossRefPubMedGoogle Scholar
  5. 5.
    Czerniecki BJ, Koski GK, Koldovsky U, Xu S, Cohen PA, Mick R, Nisenbaum H, Pasha T, Xu M, Fox KR, Weinstein S, Orel SG, Vonderheide R, Coukos G, DeMichele A, Araujo L, Spitz FR, Rosen M, Levine BL, June C, Zhang PJ (2007) Targeting HER-2/neu in early breast cancer development using dendritic cells with staged interleukin-12 burst secretion. Cancer Res 67(4):1842–1852CrossRefPubMedGoogle Scholar
  6. 6.
    Gonzalez RJ, Buzdar AU, Fraser Symmans W, Yen TW, Broglio KR, Lucci A, Esteva FJ, Yin G, Kuerer HM (2007) Novel clinical trial designs for treatment of ductal carcinoma in situ of the breast with trastuzumab (herceptin). Breast J 13(1):72–75CrossRefPubMedGoogle Scholar
  7. 7.
    Yen TW, Kuerer HM, Ottesen RA, Rouse L, Niland JC, Edge SB, Theriault RL, Weeks JC (2007) Impact of randomized clinical trial results in the national comprehensive cancer network on the use of tamoxifen after breast surgery for ductal carcinoma in situ. J Clin Oncol 25(22):3251–3258CrossRefPubMedGoogle Scholar
  8. 8.
    Page DL, Dupont WD, Rogers LW, Jensen RA, Schuyler PA (1995) Continued local recurrence of carcinoma 15–25 years after a diagnosis of low grade ductal carcinoma in situ of the breast treated only by biopsy. Cancer 76(7):1197–1200CrossRefPubMedGoogle Scholar
  9. 9.
    Gauthier ML, Berman HK, Miller C, Kozakeiwicz K, Chew K, Moore D, Rabban J, Chen YY, Kerlikowske K, Tlsty TD (2007) Abrogated response to cellular stress identifies DCIS associated with subsequent tumor events and defines basal-like breast tumors. Cancer Cell 12(5):479–491CrossRefPubMedGoogle Scholar
  10. 10.
    Hu M, Peluffo G, Chen H, Gelman R, Schnitt S, Polyak K (2009) Role of COX-2 in epithelial-stromal cell interactions and progression of ductal carcinoma in situ of the breast. Proc Natl Acad Sci USA 106(9):3372–3377CrossRefPubMedGoogle Scholar
  11. 11.
    Bissell MJ, Radisky D (2001) Putting tumours in context. Nat Rev Cancer 1(1):46–54CrossRefPubMedGoogle Scholar
  12. 12.
    Elenbaas B, Weinberg RA (2001) Heterotypic signaling between epithelial tumor cells and fibroblasts in carcinoma formation. Exp Cell Res 264(1):169–184CrossRefPubMedGoogle Scholar
  13. 13.
    Mueller MM, Fusenig NE (2004) Friends or foes—bipolar effects of the tumour stroma in cancer. Nat Rev Cancer 4(11):839–849CrossRefPubMedGoogle Scholar
  14. 14.
    Olumi AF, Grossfeld GD, Hayward SW, Carroll PR, Tlsty TD, Cunha GR (1999) Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res 59(19):5002–5011PubMedGoogle Scholar
  15. 15.
    Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, Carey VJ, Richardson AL, Weinberg RA (2005) Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121(3):335–348CrossRefPubMedGoogle Scholar
  16. 16.
    Brown LF, Guidi AJ, Schnitt SJ, Van De Water L, Iruela-Arispe ML, Yeo TK, Tognazzi K, Dvorak HF (1999) Vascular stroma formation in carcinoma in situ, invasive carcinoma, and metastatic carcinoma of the breast. Clin Cancer Res 5(5):1041–1056PubMedGoogle Scholar
  17. 17.
    Guidi AJ, Fischer L, Harris JR, Schnitt SJ (1994) Microvessel density and distribution in ductal carcinoma in situ of the breast. J Natl Cancer Inst 86(8):614–619CrossRefPubMedGoogle Scholar
  18. 18.
    Jacobs TW, Schnitt SJ, Tan X, Brown LF (2002) Radial scars of the breast and breast carcinomas have similar alterations in expression of factors involved in vascular stroma formation. Hum Pathol 33(1):29–38CrossRefPubMedGoogle Scholar
  19. 19.
    Hannemann J, Kristel P, van Tinteren H, Bontenbal M, van Hoesel QG, Smit WM, Nooij MA, Voest EE, van der Wall E, Hupperets P, de Vries EG, Rodenhuis S, van de Vijver MJ (2006) Molecular subtypes of breast cancer and amplification of topoisomerase II alpha: predictive role in dose intensive adjuvant chemotherapy. Br J Cancer 95(10):1334–1341CrossRefPubMedGoogle Scholar
  20. 20.
    Chang HY, Sneddon JB, Alizadeh AA, Sood R, West RB, Montgomery K, Chi JT, van de Rijn M, Botstein D, Brown PO (2004) Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumors and wounds. PLoS Biol 2(2):E7CrossRefPubMedGoogle Scholar
  21. 21.
    Dvorak HF (1986) Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 315(26):1650–1659CrossRefPubMedGoogle Scholar
  22. 22.
    Bhowmick NA, Moses HL (2005) Tumor-stroma interactions. Curr Opin Genet Dev 15(1):97–101CrossRefPubMedGoogle Scholar
  23. 23.
    Cunha GR, Hayward SW, Wang YZ, Ricke WA (2003) Role of the stromal microenvironment in carcinogenesis of the prostate. Int J Cancer 107(1):1–10CrossRefPubMedGoogle Scholar
  24. 24.
    Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, Richardson AL, Polyak K, Tubo R, Weinberg RA (2007) Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449(7162):557–563CrossRefPubMedGoogle Scholar
  25. 25.
    Tlsty TD, Coussens LM (2006) Tumor stroma and regulation of cancer development. Annu Rev Pathol 1:119–150CrossRefPubMedGoogle Scholar
  26. 26.
    Pavlakis K, Messini I, Vrekoussis T, Yiannou P, Keramopoullos D, Louvrou N, Liakakos T, Stathopoulos EN (2008) The assessment of angiogenesis and fibroblastic stromagenesis in hyperplastic and pre-invasive breast lesions. BMC Cancer 8:88CrossRefPubMedGoogle Scholar
  27. 27.
    Shekhar MP, Tait L, Pauley RJ, Wu GS, Santner SJ, Nangia-Makker P, Shekhar V, Nassar H, Visscher DW, Heppner GH, Miller FR (2008) Comedo-ductal carcinoma in situ: A paradoxical role for programmed cell death. Cancer Biol Ther 7(11):1774–1782Google Scholar
  28. 28.
    Rodriguez-Pinilla SM, Rodriguez-Gil Y, Moreno-Bueno G, Sarrio D, Martin-Guijarro Mdel C, Hernandez L, Palacios J (2007) Sporadic invasive breast carcinomas with medullary features display a basal-like phenotype: an immunohistochemical and gene amplification study. Am J Surg Pathol 31(4):501–508CrossRefPubMedGoogle Scholar
  29. 29.
    Vincent-Salomon A, Gruel N, Lucchesi C, MacGrogan G, Dendale R, Sigal-Zafrani B, Longy M, Raynal V, Pierron G, de Mascarel I, Taris C, Stoppa-Lyonnet D, Pierga JY, Salmon R, Sastre-Garau X, Fourquet A, Delattre O, de Cremoux P, Aurias A (2007) Identification of typical medullary breast carcinoma as a genomic sub-group of basal-like carcinomas, a heterogeneous new molecular entity. Breast Cancer Res 9(2):R24CrossRefPubMedGoogle Scholar
  30. 30.
    Qian B, Deng Y, Im JM, Muschel RJ, Zou Y, Li J, Lang RA, Pollard JW (2009) A distinct macrophage population mediates metastatic breast cancer cell extravasation, establishment and growth. PLoS ONE 4(8):e6562CrossRefPubMedGoogle Scholar
  31. 31.
    Akli S, Zheng PJ, Multani AS, Wingate HF, Pathak S, Zhang N, Tucker SL, Chang S, Keyomarsi K (2004) Tumor-specific low molecular weight forms of cyclin E induce genomic instability and resistance to p21, p27, and antiestrogens in breast cancer. Cancer Res 64(9):3198–3208CrossRefPubMedGoogle Scholar
  32. 32.
    Kenny PA, Lee GY, Bissell MJ (2007) Targeting the tumor microenvironment. Front Biosci 12:3468–3474CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • M. Sharma
    • 1
  • A. H. Beck
    • 1
  • J. A. Webster
    • 1
  • I. Espinosa
    • 1
  • K. Montgomery
    • 1
  • S. Varma
    • 2
  • M. van de Rijn
    • 1
  • K. C. Jensen
    • 1
    • 2
  • R. B. West
    • 1
    • 2
    Email author
  1. 1.Department of PathologyStanford University HospitalStanfordUSA
  2. 2.Veterans Affairs Palo Alto Health Care SystemPalo AltoUSA

Personalised recommendations