Abstract
Background Loss of the chromosomal material at 16q is the most frequent genetic event in invasive and in situ (LCIS) lobular carcinoma of the breast. However, the smallest region of overlap at 16q is not restricted to just the CDH1 locus harbouring E-cadherin, suggesting that neighbouring genes might be involved in the development and progression of these tumours. Potential novel tumour suppressor genes (TSG) at 16q include CCCTC-binding factor (CTCF), Decreased Expression in Renal and Prostate Cancer (DERPC) and Dipeptidase 1 (DPEP1). The aim of this study is to assess the expression of these genes in LCIS and compare them with normal breast, using CDH1 as a control, in order to evaluate their role as TSGs. Methods Cells from LCIS cases and normal breast lobules were microdissected and expression of target genes were quantified using real-time PCR. In addition, immunohistochemistry (IHC) for E-cadherin and CTCF was performed on paraffin processed LCIS (n = 49) and normal breast cases. Results All LCIS showed negative expression of E-cadherin. Similar to CDH1, CTCF and DPEP1 gene expression was significantly lower in LCIS cases compared with normal cases (P < 0.05). CTCF IHC expression showed significant reduction in LCIS compared to normal parenchymal cells. However, there was no difference in expression of DERPC between LCIS and normal breast tissue. Conclusions In addition to CDH1, loss of CTCF and DPEP1 gene expression suggest they are possible TSG in breast cancer and may, similar to CDH1, be potentially utilised as markers of predisposition of women diagnosed with LCIS.
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Frykberg ER (1999) Lobular carcinoma in situ of the breast. Breast J 5:296–303
Bland KI, Menck HR, Scott-Conner CE, Morrow M, Winchester DJ, Winchester DP (1998) The National Cancer Data Base 10-year survey of breast carcinoma treatment at hospitals in the United States. Cancer 83:1262–1273
Abdel-Fatah TM, Powe DG, Hodi Z, Lee AH, Reis-Filho JS, Ellis IO (2007) High frequency of coexistence of columnar cell lesions, lobular neoplasia, and low grade ductal carcinoma in situ with invasive tubular carcinoma and invasive lobular carcinoma. Am J Surg Pathol 31:417–426
Gunther K, Merkelbach-Bruse S, Amo-Takyi BK, Handt S, Schroder W, Tietze L (2001) Differences in genetic alterations between primary lobular and ductal breast cancers detected by comparative genomic hybridization. J Pathol 193:40–47
Cleton-Jansen AM (2002) E-cadherin and loss of heterozygosity at chromosome 16 in breast carcinogenesis: different genetic pathways in ductal and lobular breast cancer? Breast Cancer Res 4:5–8
Amari M, Suzuki A, Moriya T, Yoshinaga K, Amano G, Sasano H, Ohuchi N, Satomi S, Horii A (1999) LOH analyses of premalignant and malignant lesions of human breast: frequent LOH in 8p, 16q, and 17q in atypical ductal hyperplasia. Oncol Rep 6:1277–1280
Baum M (1995) Breast cancer: a guide for every women. Oxford University Press
Rakha EA, Green AR, Powe DG, Roylance R, Ellis IO (2006) Chromosome 16 tumor-suppressor genes in breast cancer. Genes Chromosomes Cancer 45:527–535
Etzell JE, Devries S, Chew K, Florendo C, Molinaro A, Ljung BM, Waldman FM (2001) Loss of chromosome 16q in lobular carcinoma in situ. Hum Pathol 32:292–296
Rakha EA, Pinder SE, Paish CE, Ellis IO (2004) Expression of the transcription factor CTCF in invasive breast cancer: a candidate gene located at 16q22.1. Br J Cancer 91:1591–1596
McIver CM, Lloyd JM, Hewett PJ, Hardingham JE (2004) Dipeptidase 1: a candidate tumor-specific molecular marker in colorectal carcinoma. Cancer Lett 209:67–74
Berx G, Becker KF, Hofler H, van Roy F (1998) Mutations of the human E-cadherin (CDH1) gene. Hum Mutat 12:226–237
Berx G, Cleton-Jansen AM, Strumane K, de Leeuw WJ, Nollet F, van Roy F, Cornelisse C (1996) E-cadherin is inactivated in a majority of invasive human lobular breast cancers by truncation mutations throughout its extracellular domain. Oncogene 13:1919–1925
Vostrov AA, Quitschke WW (1997) The zinc finger protein CTCF binds to the APBbeta domain of the amyloid beta-protein precursor promoter. Evidence for a role in transcriptional activation. J Biol Chem 272:33353–33359
Filippova GN, Fagerlie S, Klenova EM, Myers C, Dehner Y, Goodwin G, Neiman PE, Collins SJ, Lobanenkov VV (1996) An exceptionally conserved transcriptional repressor, CTCF, employs different combinations of zinc fingers to bind diverged promoter sequences of avian and mammalian c-myc oncogenes. Mol Cell Biol 16:2802–2813
Burcin M, Arnold R, Lutz M, Kaiser B, Runge D, Lottspeich F, Filippova GN, Lobanenkov VV, Renkawitz R (1997) Negative protein 1, which is required for function of the chicken lysozyme gene silencer in conjunction with hormone receptors, is identical to the multivalent zinc finger repressor CTCF. Mol Cell Biol 17:1281–1288
Kanduri C, Pant V, Loukinov D, Pugacheva E, Qi CF, Wolffe A, Ohlsson R, Lobanenkov VV (2000) Functional association of CTCF with the insulator upstream of the H19 gene is parent of origin-specific and methylation-sensitive. Curr Biol 10:853–856
Filippova GN, Qi CF, Ulmer JE, Moore JM, Ward MD, Hu YJ, Loukinov DI, Pugacheva EM, Klenova EM, Grundy PE, Feinberg AP, Cleton-Jansen AM, Moerland EW, Cornelisse CJ, Suzuki H, Komiya A, Lindblom A, Dorion-Bonnet F, Neiman PE, Morse HC 3rd, Collins SJ, Lobanenkov VV (2002) Tumor-associated zinc finger mutations in the CTCF transcription factor selectively alter tts DNA-binding specificity. Cancer Res 62:48–52
Rasko JE, Klenova EM, Leon J, Filippova GN, Loukinov DI, Vatolin S, Robinson AF, Hu YJ, Ulmer J, Ward MD, Pugacheva EM, Neiman PE, Morse HC 3rd, Collins SJ, Lobanenkov VV (2001) Cell growth inhibition by the multifunctional multivalent zinc-finger factor CTCF. Cancer Res 61:6002–6007
Kozak EM, Tate SS (1982) Glutathione-degrading enzymes of microvillus membranes. J Biol Chem 257:6322–6327
Sun M, Ma L, Xu L, Li J, Zhang W, Petrovics G, Makarem M, Sesterhenn I, Zhang M, Blanchette-Mackie EJ, Moul J, Srivastava S, Zou Z (2002) A human novel gene DERPC on 16q22.1 inhibits prostate tumor cell growth and its expression is decreased in prostate and renal tumors. Mol Med 8:655–663
Madjd Z, Pinder SE, Paish C, Ellis IO, Carmichael J, Durrant LG (2003) Loss of CD59 expression in breast tumours correlates with poor survival. J Pathol 200:633–639
McCarty KS Jr, Miller LS, Cox EB, Konrath J, McCarty KS Sr (1985) Estrogen receptor analyses. Correlation of biochemical and immunohistochemical methods using monoclonal antireceptor antibodies. Arch Pathol Lab Med 109:716–721
Lehmann U, Kreipe H (2001) Real-time PCR analysis of DNA and RNA extracted from formalin-fixed and paraffin-embedded biopsies. Methods 25:409–418
Fernandez-Gonzalez R, Jones A, Garcia-Rodriguez E, Chen PY, Idica A, Lockett SJ, Barcellos-Hoff MH, Ortiz-De-Solorzano C (2002) System for combined three-dimensional morphological and molecular analysis of thick tissue specimens. Microsc Res Tech 59:522–530
Vos CB, Cleton-Jansen AM, Berx G, de Leeuw WJ, ter Haar NT, van Roy F, Cornelisse CJ, Peterse JL, van de Vijver MJ (1997) E-cadherin inactivation in lobular carcinoma in situ of the breast: an early event in tumorigenesis. Br J Cancer 76:1131–1133
Emmert-Buck MR, Bonner RF, Smith PD, Chuaqui RF, Zhuang Z, Goldstein SR, Weiss RA, Liotta LA (1996) Laser capture microdissection. Science 274:998–1001
Mastracci TL, Tjan S, Bane AL, O’Malley FP, Andrulis IL (2005) E-cadherin alterations in atypical lobular hyperplasia and lobular carcinoma in situ of the breast. Mod Pathol 18:741–751
Aulmann S, Blaker H, Penzel R, Rieker RJ, Otto HF, Sinn HP (2003) CTCF gene mutations in invasive ductal breast cancer. Breast Cancer Res Treat 80:347–352
Austruy E, Cohen-Salmon M, Antignac C, Beroud C, Henry I, Nguyen VC, Brugieres L, Junien C, Jeanpierre C (1993) Isolation of kidney complementary DNAs down-expressed in Wilms’ tumor by a subtractive hybridization approach. Cancer Res 53:2888–2894
Klaunig JE, Xu Y, Isenberg JS, Bachowski S, Kolaja KL, Jiang J, Stevenson DE, Walborg EF Jr (1998) The role of oxidative stress in chemical carcinogenesis. Environ Health Perspect 106 1(Suppl):289–295
Hiraguri S, Godfrey T, Nakamura H, Graff J, Collins C, Shayesteh L, Doggett N, Johnson K, Wheelock M, Herman J, Baylin S, Pinkel D, Gray J (1998) Mechanisms of inactivation of E-cadherin in breast cancer cell lines. Cancer Res 58:1972–1977
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Green, A.R., Krivinskas, S., Young, P. et al. Loss of expression of chromosome 16q genes DPEP1 and CTCF in lobular carcinoma in situ of the breast. Breast Cancer Res Treat 113, 59–66 (2009). https://doi.org/10.1007/s10549-008-9905-8
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DOI: https://doi.org/10.1007/s10549-008-9905-8