TIMP-1 as a tumor marker in breast cancer – An update

Würtz, Sidse Ørnbjerg; Schrohl, Anne-Sofie; Mouridsen, Henning T.; Brünner, Nils

doi:10.1080/02841860802022976

Cited by 83 publications

(61 citation statements)

References 48 publications

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“…TIMP1 inhibits apoptosis (28)(29)(30)(31) and protects human breast epithelial cells against both intrinsic and extrinsic apoptotic cell death via the focal adhesion kinase/phosphatidylinositol 3-kinase and MAPK signaling pathways, and thus may be oncogenic (32). Clinical studies using primary breast cancer cells revealed an association between high levels of TIMP1 mRNA or protein and a poor prognosis for patients with breast cancer (33)(34)(35). In addition, TIMP1 gene deficiency increased tumor cell sensitivity to chemotherapy-induced apoptosis (36).…”

Section: Discussionmentioning

confidence: 99%

Surgical removal of the parametrial fat pads stimulates apoptosis and inhibits UVB-induced carcinogenesis in mice fed a high-fat diet

Lü

Lou

Bernard

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Removal of the parametrial fat pads (partial lipectomy) from female SKH-1 mice fed a high-fat diet inhibited UVB-induced carcinogenesis, but this was not observed in mice fed a low-fat chow diet. Partial lipectomy in high-fat-fed mice decreased the number of keratoacanthomas and squamous cell carcinomas per mouse by 76 and 79%, respectively, compared with sham-operated control mice irradiated with UVB for 33 wk. Immunohistochemical analysis indicated that partial lipectomy increased caspase 3 (active form) positive cells by 48% in precancerous epidermis away from tumors, by 68% in keratoacanthomas, and by 224% in squamous cell carcinomas compared with sham-operated control mice. In addition, partial lipectomy decreased cell proliferation away from tumors and in tumors. RT-PCR analysis for adipokines revealed that mRNAs for TIMP1, MCP1, and SerpinE1 (proinflammatory/antiapoptotic cytokines) in the parametrial fat pads of sham-operated control mice were 54-to 83-fold higher than levels in compensatory fat that returned after surgery in partially lipectomized mice at the end of the tumor study. Feeding mice high-fat diets for 2 wk increased levels of TIMP1 and other adipokines in serum and epidermis, and these increases were inhibited by removal of the parametrial fat pads. Our results are a unique demonstration that surgical removal of a specific tissue fat results in inhibition of carcinogenesis in obese mice. This inhibition was associated with an increase in apoptosis and a decrease in proliferation in tumors and in precancerous areas away from tumors.obesity | skin cancer S unlight-induced nonmelanoma skin cancer is a major cancer in the United States (1-4), and rates of obesity are also dramatically increasing, leading to an alarming rise in morbidity and mortality caused by heart disease, diabetes, and cancer. How obesity contributes to skin cancer and the molecular changes induced by obesity that promote skin cancer development remain poorly understood. Therefore, approaches for preventing these cancers are of considerable importance. Early studies in our laboratory indicated that orally administered caffeine to UVB-pretreated "high-risk" SKH-1 mice decreased tissue fat as measured by the size of the parametrial fat pads and the thickness of the dermal fat layer (5), and this treatment also decreased tumor formation (6). Mechanistic studies suggested that the stimulatory effect of caffeine administration on locomotor activity contributed to the effect of caffeine on tissue fat (7). Our results also showed that voluntary running wheel exercise decreased the weight of the parametrial fat pads, which was associated with decreased UVB-induced formation of skin tumors as well as the size of the tumors (8). Additional observations indicated that a combination of caffeine administration and running wheel exercise was more effective than either treatment alone at decreasing tissue fat and enhancing UVB-induced apoptosis (9). In a recent study, we found that running wheel exercise together with oral administration o...

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Section: Discussionmentioning

confidence: 99%

Surgical removal of the parametrial fat pads stimulates apoptosis and inhibits UVB-induced carcinogenesis in mice fed a high-fat diet

Lü

Lou

Bernard

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Contrary to what the role of TIMP-1 in inhibiting the prometastatic factor MMP-9 might suggest, high TIMP-1 levels actually correlate with a worse prognosis and a faster progression of the disease. 47,48 This phenomenon seems to be related to the capability of TIMP-1 of promoting cell survival and proliferation of cancer cells, making it an appealing target for novel therapeutic strategies for the treatment of breast cancer, as well as fibrosis secondary to hypertension 49 or liver diseases. 50,51 Although several compounds are currently under investigation as TIMP-1 inhibitors, the potential side effects of such therapeutic approaches are still controversial and poorly investigated.…”

Section: Discussionmentioning

confidence: 99%

TIMP-1 deficiency subverts cell-cycle dynamics in murine long-term HSCs

Rossi

Ergen

Goodell

2011

Blood

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In addition to the well-recognized role in extracellular matrix remodeling, the tissue inhibitor of metalloproteinases-1 (TIMP-1) has been suggested to be involved in the regulation of numerous biologic functions, including cell proliferation and survival. We therefore hypothesized that TIMP-1 might be involved in the homeostatic regulation of HSCs, whose biologic behavior is the synthesis of both microenvironmental and intrinsic cues. We found that TIMP-1 ؊/؊ mice have decreased BM cellularity and, consistent with this finding, TIMP-1 ؊/؊ HSCs display reduced capability of longterm repopulation. Interestingly, the cell cycle distribution of TIMP-1 ؊/؊ stem cells appears distorted, with a dysregulation at the level of the G 1 phase. TIMP-1 ؊/؊ HSCs also display increased levels of p57, p21, and p53, suggesting that TIMP-1 could be intrinsically involved in the regulation of HSC cycling dynamics. Of note, TIMP-1 ؊/؊ HSCs present decreased levels of CD44 glycoprotein, whose expression has been proven to be controlled by p53, the master regulator of the G 1 /S transition. Our findings establish a role for TIMP-1 in regulating HSC function, suggesting a novel mechanism presiding over stem cell quiescence in the framework of the BM milieu. (Blood. 2011;117(24):6479-6488) IntroductionThe capability of HSCs to maintain the homeostasis of the hematopoietic system is the result of a finely tuned balance between self-renewal and differentiation. The mechanisms responsible for this balance comprise both intrinsic and extrinsic factors, whose crosstalk eventually dictates the fate of stem cells in the framework of the BM niche. [1][2][3] Beside the well-established structural function, the dynamic network of interacting macromolecules that constitutes the extracellular matrix (ECM) represents one of the most powerful sources of extrinsic factors generated by the BM microenvironment. 4 The intricate architecture created by these molecules not only guarantees protection and mechanical support to the stem cell pool but also plays an active role in regulating their behavior. By binding growth factors, regulating their bioavailability, and enabling the interaction with cell-surface receptors, ECM components have been shown to modulate a variety of cellular functions, such as proliferation, survival, and differentiation. 5 ECM dynamic remodeling is controlled by metalloproteinases (MMPs), a class of Zn ϩϩ -dependent proteinases, such as collagenases, gelatinases, and stromelysins, that participate in the digestion of many ECM components, under both physiologic and pathologic conditions. 6 The enzymatic activity of MMPs is counterbalanced by several natural inhibitors, including the tissue inhibitors of metalloproteinases (TIMPs). 7 Both MMPs and TIMPs are expressed by hematopoietic and stromal cells 8 and are decisive regulators of the crosstalk between these 2 cellular entities. The mammalian TIMP family comprises 4 highly conserved members that reversibly block MMP-dependent proteolysis by forming noncovalent 1:1 stoichiometric...

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“…Clinical studies revealed somewhat contradictory results, since both high and low levels of TIMP-1 in tumor tissue extracts were associated with a poor prognosis in breast carcinoma patients [18,19] . High preoperative serum levels of TIMP-1 were also a prognosticator of a poor outcome in breast carcinoma patients [20] , and a recent review suggested a predictive role of TIMP-1 in anticancer therapies according to preclinical data and preliminary clinical studies [21] .…”

Section: Introductionmentioning

confidence: 99%

Immunohistochemical Study of Matrix Metalloproteinase 9 and Tissue Inhibitor of Matrix Metalloproteinase 1 in Benign and Malignant Breast Tissue – Strong Expression in Intraductal Carcinomas of the Breast

Rahko¹,

Kauppila²,

Pääkkö³

et al. 2009

Tumor Biol

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Objective: Matrix metalloproteinases (MMPs) are involved in carcinogenesis due to their tissue remodeling capability, and there is convincing evidence linking gelatinase B (MMP-9) with malignant cell invasion. Tissue inhibitor 1 of MMP (TIMP-1) is a strong inhibitor of MMP-9 but has also tumor-enhancing effects. Only few data exist on MMP-9 or TIMP-1 expression in tissue samples of different breast histology. Methods: MMP-9 and TIMP-1 immunoreactivity was examined in a wide range of breast tissue samples differing in histology from usual ductal hyperplasia (UDH) to fully developed ductal breast carcinoma. Immunohistochemical expression of MMP-9 was studied in 178 samples: 31 UDH samples, 29 atypical ductal hyperplasia (ADH) samples, 28 ductal carcinoma in situ (DCIS) samples and 90 ductal invasive carcinoma samples (30 samples of malignancy grades I, II and III, respectively). TIMP-1 expression was also analyzed in 178 breast tissue samples: 41 UDH, 21 ADH and 34 DCIS lesions, and 82 invasive ductal breast carcinomas (25 in grade I, 30 in grade II and 27 in grade III). Results: A significantly distinctive pattern of MMP-9 protein expression was shown in DCIS samples, where 85.7% of the cases showed moderate or strong positivity and negative staining was rare (p = 0.021). Negative or weakly positive MMP-9 staining was the most prominent finding in UDH (71%), ADH (69%) as well as in invasive carcinoma samples (64.4%). Various degrees of TIMP-1 expression were seen in 86.5% of all cases. DCIS and invasive carcinoma samples revealed similar immunostaining: at least some positivity was seen in 91.1% of the DCIS samples and 91.5% of infiltrative carcinomas. Thus, TIMP-1 negativity (22.2%) was significantly associated with hyperplastic lesions (p = 0.026). Conclusions: These results suggest that MMP-9 and TIMP-1 overexpression are early markers of breast carcinogenesis preceding tumor invasion. Apparently, DCIS carries the risk to evolve into a malignant phenotype according to these markers. The clinical importance of these findings is discussed.

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TIMP-1 as a tumor marker in breast cancer – An update

Cited by 83 publications

References 48 publications

Surgical removal of the parametrial fat pads stimulates apoptosis and inhibits UVB-induced carcinogenesis in mice fed a high-fat diet

Surgical removal of the parametrial fat pads stimulates apoptosis and inhibits UVB-induced carcinogenesis in mice fed a high-fat diet

TIMP-1 deficiency subverts cell-cycle dynamics in murine long-term HSCs

Immunohistochemical Study of Matrix Metalloproteinase 9 and Tissue Inhibitor of Matrix Metalloproteinase 1 in Benign and Malignant Breast Tissue – Strong Expression in Intraductal Carcinomas of the Breast

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