Introduction. Despite advances in breast cancer systemic treatment, new prognostic and predictive factors are still needed. Tissue inhibitor of metalloproteinase-1 (TIMP-1), a physiologic inhibitor of matrix metalloproteinases (MMPs), can act in both pro- and antitumoral effects. As role of TIMP-1 in breast cancer is controversial, we aimed to determine the prognostic significance of TIMP-1 in breast cancer. Methods. A single center-based case-control study was applied. Primary breast cancers from women with early stage disease treated with standard adjuvant therapy were analyzed by gene expression microarrays and immunohistochemistry for TIMP-1. Results. At the optimized cut-point, patients with high TIMP-1 RNA levels had a significantly shorter time to relapse, with a hazard ratio (HR) of 1.64 ( ？？ = 0 . 0 4 ), but without significant differences in overall survival (HR 1.29, ？ = 0 . 3 7 ). Although cytoplasmic overexpression of TIMP-1 protein was not correlated with early relapse (HR 1.0, ？？ = 0 . 9 2 ), there was a tendency for short overall survival in patients with high expression (HR 1.41, ？？ = 0 . 2 1 ). Conclusions. Our data indicate that elevated TIMP-1 RNA levels are independently prognostic for early recurrence, and there is a tendency for association of high cytoplasmic TIMP-1 protein levels with short survival in primary breast cancer. 1. Introduction Breast cancer is the second most common cause of cancer death in women, with more than 1 million new cases of breast cancer diagnosed each year [1]. In 2011, more than 23,000 Canadian women were newly diagnosed with breast cancer and 5,100 women died from this disease [2]. Breast cancer is a heterogeneous disease characterized by varying morphological appearances, molecular features, and response to therapy [3]. Adjuvant systemic therapy in women with early stage disease is guided by prognostic and predictive factors, including stage, grade, estrogen receptor (ER) and progesterone receptor (PR) status, and HER2 amplification. These parameters help physicians to select adjuvant systemic therapy. However, these remain imperfect tools, in that some patients receive systemic chemotherapy even though they can be cured by surgery alone. In contrast, those who were categorized in low-risk group had short disease-free survival without receiving adjuvant chemotherapy. Therefore, new prognostic and predictive factors are still required to optimize treatments among these patients. Tissue inhibitor of metalloproteinases-1 (TIMP-1) is one of four natural inhibitors of the matrix metalloproteinases (MMPs),
References
[1]
P. Porter, ““Westernizing” women's risks? Breast cancer in lower-income countries,” New England Journal of Medicine, vol. 358, no. 3, pp. 213–216, 2008.
[2]
Canadian Cancer Society’s Steering Committee on Cancer Statistics, Canadian Cancer Statistics. Canadian Cancer Society Toronto, ON, Canada, 2011.
[3]
E. A. Rakha, J. S. Reis-Filho, F. Baehner et al., “Breast cancer prognostic classification in the molecular era: the role of histological grade,” Breast Cancer Research, vol. 12, no. 4, p. 207, 2010.
[4]
S. ？. Würtz, A. S. Schrohl, N. M？ller S？rensen et al., “Tissue inhibitor of metalloproteinases-1 in breast cancer,” Endocrine-Related Cancer, vol. 12, no. 2, pp. 215–227, 2005.
[5]
S. ？. Würtz, A. S. Schrohl, H. Mouridsen, and N. Brünner, “TIMP-1 as a tumor marker in breast cancer—an update,” Acta Oncologica, vol. 47, no. 4, pp. 580–590, 2008.
[6]
Z. S. Wu, Q. Wu, J. H. Yang et al., “Prognostic significance of MMP-9 and TIMP-1 serum and tissue expression in breast cancer,” International Journal of Cancer, vol. 122, no. 9, pp. 2050–2056, 2008.
[7]
K. McCarthy, T. Maguire, G. McGreal, et al., “High levels of tissue inhibitor of metalloproteinase-1 predict poor outcome in patients with breast cancer,” International Journal of Cancer, vol. 84, no. 1, pp. 44–48, 1999.
[8]
P. Kuvaja, S. ？. Würtz, A. Talvensaari-Mattila, N. Brünner, P. P？？kk？, and T. Turpeenniemi-Hujanen, “High serum TIMP-1 correlates with poor prognosis in breast carcinoma—a validation study,” Cancer Biomarkers, vol. 3, no. 6, pp. 293–300, 2007.
[9]
A. S. Schrohl, I. J. Christensen, A. N. Pedersen et al., “Tumor tissue concentrations of the proteinase inhibitors tissue inhibitor of metalloproteinases-1 (TIMP-1) and plasminogen activator inhibitor type 1 (PAI-1) are complementary in determining prognosis in primary breast cancer,” Molecular & Cellular Proteomics, vol. 2, no. 3, pp. 164–172, 2003.
[10]
A. S. Schrohl, M. N. Holten-Andersen, H. A. Peters et al., “Tumor tissue levels of tissue inhibitor of metalloproteinase-1 as a prognostic marker in primary breast cancer,” Clinical Cancer Research, vol. 10, no. 7, pp. 2289–2298, 2004.
[11]
A. Talvensaari-Mattila and T. Turpeenniemi-Hujanen, “High preoperative serum TIMP-1 is a prognostic indicator for survival in breast carcinoma,” Breast Cancer Research and Treatment, vol. 89, no. 1, pp. 29–34, 2005.
[12]
S. ？. Würtz, S. M？ller, H. Mouridsen, P. B. Hertel, E. Friis, and N. Brünner, “Plasma and serum levels of tissue inhibitor of metalloproteinases-1 are associated with prognosis in node-negative breast cancer: a prospective study,” Molecular and Cellular Proteomics, vol. 7, no. 2, pp. 424–430, 2008.
[13]
A. S. Schrohl, M. E. Meijer-Van Gelder, M. N. Holten-Andersen et al., “Primary tumor levels of tissue inhibitor of metalloproteinases-1 are predictive of resistance to chemotherapy in patients with metastatic breast cancer,” Clinical Cancer Research, vol. 12, no. 23, pp. 7054–7058, 2006.
[14]
A. Lipton, K. Leitzel, H. A. Chaudri-Ross et al., “Serum TIMP-1 and response to the aromatase inhibitor letrozole versus tamoxifen in metastatic breast cancer,” Journal of Clinical Oncology, vol. 26, no. 16, pp. 2653–2658, 2008.
[15]
L. Nakopoulou, I. Giannopoulou, A. C. Lazaris et al., “The favorable prognostic impact of tissue inhibitor of matrix metalloproteinases-1 protein overexpression in breast cancer cells,” Acta Pathologica, Microbiologica, et Immunologica Scandinavica, vol. 111, no. 11, pp. 1027–1036, 2003.
[16]
A. M. Sieuwerts, P. A. Usher, M. E. Meijer-Van Gelder et al., “Concentrations of TIMP1 mRNA splice variants and TIMP-1 protein are differentially associated with prognosis in primary breast cancer,” Clinical Chemistry, vol. 53, no. 7, pp. 1280–1288, 2007.
[17]
D. R. Germain, K. Graham, D. D. Glubrecht, J. C. Hugh, J. R. MacKey, and R. Godbout, “DEAD box 1: a novel and independent prognostic marker for early recurrence in breast cancer,” Breast Cancer Research and Treatment, vol. 127, no. 1, pp. 53–63, 2011.
[18]
R. Z. Liu, K. Graham, D. D. Glubrecht, D. R. Germain, J. R. Mackey, and R. Godbout, “Association of FABP5 expression with poor survival in triple-negative breast cancer: implication for retinoic acid therapy,” American Journal of Pathology, vol. 178, no. 3, pp. 997–1008, 2011.
[19]
L. Nakopoulou, I. Giannopoulou, K. Stefanaki et al., “Enhanced mRNA expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) in breast carcinomas is correlated with adverse prognosis,” Journal of Pathology, vol. 197, no. 3, pp. 307–313, 2002.
[20]
G. L. Willemoe, P. B. Hertel, A. Bartels et al., “Lack of TIMP-1 tumour cell immunoreactivity predicts effect of adjuvant anthracycline-based chemotherapy in patients () with primary breast cancer. A Danish Breast Cancer Cooperative Group Study,” European Journal of Cancer, vol. 45, no. 14, pp. 2528–2536, 2009.
[21]
B. Ejlertsen, M. B. Jensen, K. V. Nielsen et al., “HER2, TOP2A, and TIMP-1 and responsiveness to adjuvant anthracycline- containing chemotherapy in high-risk breast cancer patients,” Journal of Clinical Oncology, vol. 28, no. 6, pp. 984–990, 2010.
[22]
B. Ejlertsen, M. B. Jensen, K. V. Nielsen et al., “HER2, TOP2A, and TIMP-1 and responsiveness to adjuvant anthracycline- containing chemotherapy in high-risk breast cancer patients,” Journal of Clinical Oncology, vol. 28, no. 6, pp. 984–990, 2010.
[23]
K. M. Fong, Y. Kida, P. V. Zimmerman, and P. J. Smith, “TIMP1 and adverse prognosis in non-small cell lung cancer,” Clinical Cancer Research, vol. 2, no. 8, pp. 1369–1372, 1996.
[24]
V. Gouyer, M. Conti, P. Devos et al., “Tissue inhibitor of metalloproteinase 1 is an independent predictor of prognosis in patients with nonsmall cell lung carcinoma who undergo resection with curative intent,” Cancer, vol. 103, no. 8, pp. 1676–1684, 2005.
[25]
N. Yukawa, T. Yoshikawa, M. Akaike et al., “Prognostic impact of tissue inhibitor of matrix metalloproteinase-1 in plasma of patients with colorectal cancer,” Anticancer Research, vol. 24, no. 3, pp. 2101–2105, 2004.
[26]
N. Yukawa, T. Yoshikawa, M. Akaike et al., “Impact of plasma tissue inhibitor of matrix metalloproteinase-1 on long-term survival in patients with colorectal cancer,” Oncology, vol. 72, no. 3-4, pp. 205–208, 2008.
[27]
N. M？ller S？rensen, I. Vejgaard S？rensen, S. ？rnbjerg Wurtz et al., “Biology and potential clinical implications of tissue inhibitor of metalloproteinases-1 in colorectal cancer treatment,” Scandinavian Journal of Gastroenterology, vol. 43, no. 7, pp. 774–786, 2008.
[28]
T. Yoshikawa, A. Tsuburaya, O. Kobayashi et al., “Prognostic value of tissue inhibitor of matrix metalloproteinase-1 in plasma of patients with gastric cancer,” Cancer Letters, vol. 151, no. 1, pp. 81–86, 2000.
[29]
T. Yoshikawa, H. Cho, A. Tsuburaya, and O. Kobayashi, “Impact of plasma tissue inhibitor of metalloproteinase-1 on long-term survival in patients with gastric cancer,” Gastric Cancer, vol. 12, no. 1, pp. 31–36, 2009.
[30]
C. A. Scrideli, M. A. A. Cortez, J. A. Yunes et al., “mRNA expression of matrix metalloproteinases (MMPs) 2 and 9 and tissue inhibitor of matrix metalloproteinases (TIMPs) 1 and 2 in childhood acute lymphoblastic leukemia: potential role of TIMP1 as an adverse prognostic factor,” Leukemia Research, vol. 34, no. 1, pp. 32–37, 2010.
[31]
Y. Jiang, I. D. Goldberg, and Y. E. Shi, “Complex roles of tissue inhibitors of metalloproteinases in cancer,” Oncogene, vol. 21, no. 14, pp. 2245–2252, 2002.
[32]
K. Yamashita, M. Suzuki, H. Iwata et al., “Tyrosine phosphorylation is crucial for growth signaling by tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2),” FEBS Letters, vol. 396, no. 1, pp. 103–107, 1996.
[33]
T. Wang, K. Yamashita, K. Iwata, and T. Hayakawa, “Both tissue inhibitors of metalloproteinases-1 (TIMP-1) and TIMP-2 activate Ras but through different pathways,” Biochemical and Biophysical Research Communications, vol. 296, no. 1, pp. 201–205, 2002.
[34]
K. K. Jung, X. W. Liu, R. Chirco, R. Fridman, and H. R. C. Kim, “Identification of CD63 as a tissue inhibitor of metalloproteinase-1 interacting cell surface protein,” EMBO Journal, vol. 25, no. 17, pp. 3934–3942, 2006.
[35]
W. G. Stetler-Stevenson, “Tissue inhibitors of metalloproteinases in cell signaling: metalloproteinase-independent biological activities,” Science Signaling, vol. 1, no. 27, article re6, 2008.
[36]
H. Li, K. Nishio, K. Yamashita, T. Hayakawa, and T. Hoshino, “Cell cycle-dependent localization of tissue inhibitor of metalloproteinases-1 immunoreactivity in cultured human gingival fibroblasts,” Nagoya Journal of Medical Science, vol. 58, no. 3-4, pp. 133–142, 1995.
[37]
P. Kuvaja, S. Hulkkonen, I. Pasanen, et al., “Tumor tissue inhibitor of metalloproteinases-1 (TIMP-1) in hormone-independent breast cancer might originate in stromal cells, and improves stratification of prognosis together with nodal status,” Experimental Cell Research, vol. 318, no. 10, pp. 1094–1103, 2012.
