Hedgehog signaling and response to cyclopamine differs in epithelial and stromal cells in benign breast and breast cancer

Mukherjee, Shibani; Frolova, Natalya; Sadlonova, Andrea; Novák, Zdeněk; Steg, Adam D.; Page, Grier P.; Welch, Danny R.; Lobo-Ruppert, Susan M.; Ruppert, J. Michael; Johnson, Martin R.; Frost, Andra R.

doi:10.4161/cbt.5.6.2906

Cited by 146 publications

(169 citation statements)

References 46 publications

(59 reference statements)

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“…SHH is active only in stem cells and/or endodermal progenitor in adults (16,23). Recent studies showed that aberrant signaling of this pathway is involved in a variety of human cancers (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). The HH pathway essentially consists of PTCH, the motive protein, SMOH, and the transcriptional factors GLI2 and GLI3.…”

Section: Discussionmentioning

confidence: 99%

“…The HH activation has been observed in other types cancers such as basal cell carcinomas of the skin (6-9), prostate cancer (10,11), lung cancer (12,13), gastrointestinal cancers (14)(15)(16)(17)(18)(19), breast cancer (20,21), and ovarian cancer (22). Although, it is required in liver embryogenesis (14,23), the HH signaling pathway is not well-sustained in the adult liver because of the insufficient HH pathway activity of mature hepatocytes (1,23).…”

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confidence: 99%

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Activation of sonic hedgehog signaling pathway is an independent potential prognosis predictor in human hepatocellular carcinoma patients

Li¹,

Che²,

Yanhua³

et al. 2012

Chin. J. Cancer Res.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Activation of sonic hedgehog signaling pathway is an independent potential prognosis predictor in human hepatocellular carcinoma patients

Li¹,

Che²,

Yanhua³

et al. 2012

Chin. J. Cancer Res.

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“…Recent work from Sarah Hatsell has demonstrated the importance of repressing Hedgehog signaling for the normal development of the embryonic mammary gland whereas Andra Frost has shown that Hedgehog activation occurs in breast carcinoma [21,22]. This article reviews recent data that show that failure to repress Hedgehog activation in carcinoma cells and stromal misactivation of Hedgehog signaling critically influence tumor progression in both human and mouse models of cancer.…”

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confidence: 92%

Breast Cancer Progression: Controversies and Consensus in the Molecular Mechanisms of Metastasis and EMT

Cowin

Welch

2007

J Mammary Gland Biol Neoplasia

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Breast cancer is the second most frequent form of female cancer and a major source of cancer death worldwide. Although breast cancer has long been part of the human condition, appearing in the writings of ancient Egyptians, modern breast cancer shows a disturbing statistical increase from 1 per 20 women in the 1960s to one in eight today [1]. Although early detection by mammography and adjuvant therapies has improved survival, the absence of good prognostic criteria continues to result in overtreatment of patients with benign disease and failure to identify and eliminate the source of metastatic breast cancer.This issue is concerned with the myriad stages of tumor progression that lead to the dissemination of breast cancer cells from the primary tumor and propagation at distant sites. The first stage in this progression involves loss of local constraints, both physical and regulatory, emanating from neighboring normal cells and surrounding stroma. The second step termed intravasation, involves entering a circulatory system (blood and/or lymphatic), the third dissemination and survival within hostile ectopic environments, and the fourth organotropic colonization of compatible sites.Considerable debate has arisen between elements in the scientific and clinical community concerning the proposed mechanisms of metastatic spread [2,3]. The controversy centers on whether metastasis involves inappropriate transient re-enactment of developmental migratory processes; Darwinian selection within a population of genomically unstable, rapidly evolving cancer cells for attributes that facilitate growth in and exploitation of new environs; or a combination of both.Seeing parallels between the metastatic process and the long-distance migration of cells during development, cell and developmental biologists have invoked epithelial-mesenchymal transition (EMT) as the mechanistic basis for breast cancer metastasis [4][5][6]. In its strictest sense, EMT and its converse MET, have been used to describe conversions in cell shape and migratory behavior that accompany cell fate changes during embryonic development. A classical example of EMT is the emergence from the coherent neural plate of migratory neural crest cells, which travel long distances and adopt many different mesenchymal cell fates. These events involve the loss of "epithelial" characteristics such as cell-cell adhesion mechanisms and junctions and switching on of vimentin expression as the major intermediate filament protein. Further analyses have revealed the essential role of a genetic program tightly

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“…Gli1 is a transcriptional activator [18] , which induces the expression of numerous target genes that regulates proliferation, differentiation, and extracellular matrix interactions [19,20] . Increasing evidence has demonstrated that the Hh signaling pathway plays an important role in multiple tumor types, for example, basal cell carcinoma [21,22] , pancreatic cancer [23] , colon carcinoma [24] , gastric cancer [25] , small cell lung cancer [26] , prostate cancer [27][28][29] , breast cancer [30,31] , early childhood hepatoblastoma [32] , and esophageal cancers [33] .…”

Section: Introductionmentioning

confidence: 99%

Hedgehog signaling pathway mediates invasion and metastasis of hepatocellular carcinoma via ERK pathway

Lü

Zhao

et al. 2012

Acta Pharmacol Sin

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Aim: To investigate the role of Hedgehog (Hh) signaling pathway in the invasion and metastasis of human hepatocellular carcinoma (HCC). Methods: Eighty six HCC tissues samples and HCC cell line Bel-7402 were examined. The protein expression of sonic hedgehog (Shh), nuclear glioma-associated oncogene-1 (Gli1), MMP-9 and p-ERK1/2 in HCC was analyzed using immunohistochemistry and Western blot analysis. Boyden chamber assay and wound-healing assay were used to quantify the invasion and metastasis of Bel-7402 cells. Results: In 86 HCC tissue samples, the positive ratio of Shh and nucleus Gli1 was 67.44% (58/86) and 60.47% (52/86), respectively; the expression of nucleus Gli1 was correlated with the tumor pathological grade (P=0.034), and with the ability of the tumor to invade and metastasize (P=0.001); the expression of nucleus Gli1 was also correlated with p-ERK1/2 (P=0.031) and with MMP-9 (P=0.034). Neither Shh, nor nucleus Gli1 was observed in normal liver tissue. KAAD-cyclopamine (KAAD-cyc), a specific inhibitor of the Hh pathway, at the concentrations of 1 and 4 μmol/L inhibited the invasion and migration of Bel-7402 cells and decreased the expression of Gli1 in nucleus and MMP-9, p-ERK1/2 proteins in Bel-7402 cells. On the other hand, Shh, a ligand of the Hh pathway, at the concentration of 0.5 μg/mL produced opposite effects. The MAPK pathway inhibitors U0126 and PD98059 at the concentrations of 5 and 10 μmol/L inhibited invasion and metastasis of Bel-7402 cells induced by Shh, and decreased the expression of p-ERK1/2 and MMP-9. However, U0126 and PD98059 had no effect on the expression of Gli1. Conclusion: Hh signaling pathway mediates invasion and metastasis of human HCC by up-regulating the protein expression of MMP-9 via ERK pathway.

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Hedgehog signaling and response to cyclopamine differs in epithelial and stromal cells in benign breast and breast cancer

Cited by 146 publications

References 46 publications

Activation of sonic hedgehog signaling pathway is an independent potential prognosis predictor in human hepatocellular carcinoma patients

Activation of sonic hedgehog signaling pathway is an independent potential prognosis predictor in human hepatocellular carcinoma patients

Breast Cancer Progression: Controversies and Consensus in the Molecular Mechanisms of Metastasis and EMT

Hedgehog signaling pathway mediates invasion and metastasis of hepatocellular carcinoma via ERK pathway

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