Expression of the Transcriptional Coregulator FHL2 in Human Breast Cancer: A Clinicopathologic Study

Gabriel, Boris; Fischer, Dagmar‐C.; Orlowska-Volk, Marzenna; Hausen, Axel zur; Schüle, Roland; Müller, Judith; Hasenburg, A.

doi:10.1016/j.jsgi.2005.10.001

Cited by 36 publications

(40 citation statements)

References 28 publications

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“…These data are in good agreement with and extend the recently published immunohistochemical investigation of FHL2 expression in breast cancer tissue. 40 Statistical evaluation performed by these authors showed further that overexpression of FHL2 in breast cancer is associated with poor survival prognosis. 23 Our findings together with these observations indicate that the FHL2 level in tumor cells reflects carcinogenic progression towards the malignant state.…”

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confidence: 97%

“…40 Statistical evaluation performed by these authors showed further that overexpression of FHL2 in breast cancer is associated with poor survival prognosis. 23 Our findings together with these observations indicate that the FHL2 level in tumor cells reflects carcinogenic progression towards the malignant state. Nevertheless, little is known about the function of FHL2 in mammary tumors and breast cancer cells.…”

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confidence: 97%

“…These standardized Western blot data are consistent with the recently described overexpression of FHL2 shown by immunohistochemical analysis of 85 breast tumors. 23 To analyze the function of FHL2 in cultured cells, we examined the expression level of FHL2 in different breast cancer cell lines by Western blot (Fig. 1C).…”

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confidence: 99%

“…20 In contrast, an overexpression of FHL2 has been reported for epithelial ovarian cancer, 21 lung cancer 22 and breast cancer. 23 In monkey kidney cells and mouse fibroblasts, FHL2 associates with c-jun and c-fos, two components of the AP1 transcription factor, and this interaction leads to activation of AP1-dependent transcription. Furthermore, FHL2 expression can be stimulated by serum in mouse fibroblasts and HeLa cells.…”

Section: Introductionmentioning

confidence: 99%

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FHL2 Regulates Cell Cycle-Dependent and Doxorubicin-Induced p21Cip1/Waf1 Expression in Breast Cancer Cells

Martin¹,

Kleiber²,

Wixler³

et al. 2007

Cell Cycle

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© 2 0 0 7 L A N D E S B I O S C I E N C E . D O N O T D I S T R I B U T E .[Cell Cycle 6:14, 1779-1788, 15 ABSTRAcTThe transcriptional cofactor FHL2 interacts with a broad variety of transcription factors and its expression is often deregulated in various types of cancer. Here we analyzed for the first time the molecular function of FHL2 in breast cancer. FHL2 is overexpressed in almost all human mammary carcinoma samples tested but not in normal breast tissues and only low levels of FHL2 expression were present in four premalignant ductal carcinoma in situ (DCIS). Cell cycle analysis revealed an upregulation of endogenous FHL2 towards G 2 /M in MDA-MB 231 cells and an accelerated G 2 /M transition when FHL2 expression was suppressed in these cells. In search for G 2 /M specific target genes regulated by FHL2, we found that expression of the cell cycle inhibitor p21 Cip1/Waf1 (hereafter p21) is dependent on FHL2 in MDA-MB 231 breast cancer cells. Downregulation of FHL2 by shRNA abrogated the cell cycle dependent upregulation of p21 as well as the induction of p21 in response to treatment with the DNA damaging agent doxorubicin. FHL2-dependent p21 expression occurs in a p53-independent manner and p21 expression can be downregulated by specific inhibition of mitogen-activated protein kinases (MAPKs), implicating an involvement of MAPK signaling in this regulation. Analysis of FHL2 contribution to the MAPK signaling identified FHL2 as an important downstream effector of MAPKs in breast cancer cells, capable of transactivating endogenous AP1 target genes as well as AP1 dependent reporter genes. Finally, downregulation of FHL2 reduces the ability of MDA-MB 231 cells to form colonies in soft agar, while FHL2 overexpression enhances colony formation of breast cancer cells. Thus, our findings indicate that overexpression of the transcriptional cofactor FHL2 contributes to breast cancer development by mediating transcriptional activation of MAPK target genes known to be involved in cancer progression, such as p21.

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Section: © 2 0 0 7 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 97%

Section: © 2 0 0 7 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 97%

Section: © 2 0 0 7 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

FHL2 Regulates Cell Cycle-Dependent and Doxorubicin-Induced p21Cip1/Waf1 Expression in Breast Cancer Cells

Martin¹,

Kleiber²,

Wixler³

et al. 2007

Cell Cycle

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“…[12][13][14][15] A number of studies from our laboratory and other groups provide evidence that FHL2 is involved in cancer progression. [16][17][18][19][20][21] Elevated expression of FHL2 and interaction with focal adhesion kinase (FAK) was found in human ovarian cancers, indicating a role of FHL2 and FAK complex during ovarian tumour progression. 17 We showed recently that activation of nuclear FHL2 signalling is linked to an aggressive biology and recurrence of prostate cancer.…”

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FHL2 expression in peritumoural fibroblasts correlates with lymphatic metastasis in sporadic but not in HNPCC-associated colon cancer

Gullotti

Czerwitzki

Kirfel

et al. 2011

Laboratory Investigation

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Four and a half LIM domain protein-2 (FHL2) is a component of the focal adhesion structures and has been suggested to have an important role in cancer progression. This study analyses the role of FHL2 in peritumoural fibroblasts of sporadic and hereditary non-polyposis colorectal cancer (HNPCC). Tissue specimens of 48 sporadic and 49 hereditary colon cancers, respectively, were stained immunohistochemically for FHL2, transforming growth factor (TGF)-b1 ligand and a-SMA. Myofibroblasts at the tumour invasion front co-expressed a-SMA and FHL2. Sporadic colon cancer but not HNPCC cases showed a correlation between TGF-b1 expression of the invading tumour cells and FHL2 staining of peritumoural myofibroblasts. Overexpression of FHL2 in peritumoural myofibroblasts correlated to lymphatic metastasis in sporadic colon cancer but not in HNPCC. In cultured mouse fibroblasts, TGF-b1 treatment induced myofibroblast differentiation, stimulated FHL2 protein expression and elevated number of migratory cells in transwell motility assays, suggesting that FHL2 is regulated downstream of TGF-b. Physical contact of colon cancer cells and myofibroblasts via FHL2-positive focal adhesions was detected in human colon carcinoma tissue and in co-culture assays using sporadic as well as HNPCC-derived tumour cell lines. Our data provide strong evidence for an important role of FHL2 in the progression of colon cancers. Tumour-secreted TGF-b1 stimulates FHL2 protein expression in peritumoural fibroblasts, probably facilitating the invasion of tumour glands into the surrounding tissue by enhanced myofibroblast migration and tight connection of fibroblasts to tumour cells via focal adhesions. These findings are absent in HNPCC-associated colon cancers in vivo and may contribute to a less invasive and more protruding tumour margin of microsatellite instable carcinomas. Four and a half LIM domain protein-2 (FHL2) was first identified as a protein differentially expressed in human myoblasts and rhabdomyosarcoma cells, and thus named DRAL (downregulated in rhabdomyosarcoma LIM protein 1 ). FHL2 is a LIM-only protein with four complete and one N-terminal half LIM domains that mediate protein-protein interactions. 2 FHL2 associates with integrin receptors to form focal adhesion contacts and binds signal transducers such as b-catenin. 3-5 Triggered by lipid-induced signalling, such as sphingosine-1-phosphate, FHL2 translocates into the nucleus where it binds several transcription factors including serum response factor, AP1 and androgen receptor and functions as a coactivator or a corepressor to modulate gene expression. [6][7][8] We showed previously that FHL2 is strongly upregulated in mesenchymal cells of wounded skin, and demonstrated a function of FHL2 in myofibroblasts regulating their migration and contraction during cutaneous wound healing. 9 Furthermore, FHL2 is critically involved in matrix assembly allowing migration of cells into the wound area. 10 Analogous to wound healing invasive carcinomas generate a specialised tumour stroma and de...

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The four‐and‐a‐half‐LIM protein 2 (FHL2) is overexpressed in gliomas and associated with oncogenic activities

Wang

et al. 2008

Glia

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Four-and-a-half-LIM protein 2 (FHL2) is a member of FHL protein family, which plays a crucial role in regulating gene expression, cell survival, and migration. Although its function in oncogenesis appears to be tumor type-specific, its roles in glioma formation and development are yet to be elucidated. In the present study, we demonstrated that the mRNA level of FHL2 was elevated in both low- and high-grade glioma samples. Overexpression of FHL2 stimulated the proliferation, anchorage-independent growth, and migration of human glioblastoma cells. Conversely, FHL2 knockdown by short hairpin RNA (shRNA-FHL2) inhibited glioblastoma cell proliferation and migration. Overexpression of FHL2 increased the tumorigenicity of glioblastoma cells in nude mice and decreased the mRNA levels of p53 and its downstream proapoptotic genes, including p21, Bcl2-associated protein X (Bax), and p53-upregulated modulator of apoptosis. It also enhanced the promoter activities of activator protein-1 (AP-1), human telomerase reverse transcriptase, and survivin genes. Together, these results provide the first evidence that FHL2 contributes to glioma carcinogenesis.

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Expression of the Transcriptional Coregulator FHL2 in Human Breast Cancer: A Clinicopathologic Study

Cited by 36 publications

References 28 publications

FHL2 Regulates Cell Cycle-Dependent and Doxorubicin-Induced p21Cip1/Waf1 Expression in Breast Cancer Cells

FHL2 Regulates Cell Cycle-Dependent and Doxorubicin-Induced p21Cip1/Waf1 Expression in Breast Cancer Cells

FHL2 expression in peritumoural fibroblasts correlates with lymphatic metastasis in sporadic but not in HNPCC-associated colon cancer

The four‐and‐a‐half‐LIM protein 2 (FHL2) is overexpressed in gliomas and associated with oncogenic activities

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