Combination of Cyclopamine and Tamoxifen Promotes Survival and Migration of MCF-7 Breast Cancer Cells – Interaction of Hedgehog-Gli and Estrogen Receptor Signaling Pathways

Sabol, Maja; Trnski, Diana; Užarević, Zvonimir; Ozretić, Petar; Musani, Vesna; Rafaj, Maja; Cindrić, Mario; Levanat, Sonja

doi:10.1371/journal.pone.0114510

Cited by 22 publications

(25 citation statements)

References 53 publications

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“…Exogenous SHH stimulation shows no direct effect on gene expression of Hedgehog pathway genes, but it positively affects the migratory potential of the cells. It is possible that the SHH ligand binds to an alternative target and stimulates cell migration, as we have shown recently on breast cancer (42), and this effect should be investigated further. Endogenous stimulation of the pathway by GLI1 results in upregulation of PTCH1 and GLI2/3.…”

Section: Discussionmentioning

confidence: 90%

Non-canonical Hedgehog signaling activation in ovarian borderline tumors and ovarian carcinomas

Ozretić

Trnski

Musani

et al. 2017

International Journal of Oncology

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Hedgehog signaling pathway has been implicated in the pathology of ovarian cancer, and Survivin (BIRC5) has been suggested as a novel target of this pathway. Herein we investigated the role of Hedgehog signaling pathway and Survivin in ovarian carcinoma and borderline tumor samples. We aimed to determine possible ways of pathway modulation on primary ovarian cancer cells and an established cell line. RNA was extracted from fresh tumors and control tissues and gene expression was examined using qRT-PCR. Pathway activity in cell lines was examined after treatment with cyclopamine, SHH protein, GANT-61 or lithium chloride using qRT-PCR, western blot and confocal microscopy. The difference between control tissue, borderline tumors and carcinomas can be seen in GLI1 and SUFU gene expression, which is significantly higher in borderline tumors compared to carcinomas. SUFU also shows lower expression levels in higher FIGO stages relative to lower stages. BIRC5 is expressed in all tumors and in healthy ovarian tissues compared to our control tissue, healthy fallopian tube samples. Primary cells developed from ovarian carcinoma tissue respond to cyclopamine treatment with a short-term decrease in cell proliferation, downregulation of Hedgehog pathway genes, including BIRC5, and changes in protein dynamics. Stimulation with SHH protein results in increased cell migration, while GLI1 transfection or PTCH1 silencing demonstrate pathway upregulation. The pathway activity can be modulated by LiCl at the GSK3β-SUFU-GLI level, suggesting at least partial non-canonical activation. Downregulation of the pathway with GANT-61 has proved to be more effective than cyclopamine. GLI inhibitors may be a superior treatment option in ovarian cancer compared to SMO inhibitors.

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Section: Discussionmentioning

confidence: 90%

Non-canonical Hedgehog signaling activation in ovarian borderline tumors and ovarian carcinomas

Ozretić

Trnski

Musani

et al. 2017

International Journal of Oncology

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“…Previous studies have reported that the Hh signaling pathway participates in various tumor processes, including formation, development, metastasis and angiogenesis (38)(39)(40). In the present study, the expression of the molecules involved in the Hh signaling pathway was investigated, and the results revealed that GLI1, PTCH1, SMO and SHh were overexpressed in cervical cancer tissues (squamous carcinoma vs. normal cervical tissue, all P<0.01; adenocarcinoma vs. normal cervical tissue, P=0.014, P=0.007, P=0.007 and P=0.007, respectively).…”

Section: A B C D E F G Hmentioning

confidence: 99%

Association between FOXM1 and hedgehog signaling pathway in human cervical carcinoma by tissue microarray analysis

et al. 2016

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Abstract. Forkhead box M1 (FOXM1) and hedgehog (Hh) signaling pathway are implicated in the formation and development of human tumors, including cervical cancer. Previous studies have indicated that FOXM1 may be a downstream target gene of the Hh signaling pathway, but their association in cervical cancer is largely unknown. In the present study, the expression of FOXM1 and Hh signaling molecules was evaluated by immunohistochemical analysis in a tissue microarray that contained 70 cervical cancer tissues and 10 normal cervical tissues. In addition, the association of these molecules with clinicopathological parameters, and the association between FOXM1 and various molecules involved in the Hh signaling pathway was investigated. The results indicated that FOXM1 and Hh signaling molecules were overexpressed in cervical cancer tissues. The protein expression levels of FOXM1, glioma-associated oncogene 1 (GLI1) and smoothened (SMO) correlated with the clinical stage of the tumors, while the protein expression levels of Sonic Hh (SHh), patched 1 (PTCH1) and GLI1 correlated with the pathological grade of the tumors. The expression levels of GLI1 were lower in tissues without lymph node metastasis than in tissues with lymph node metastasis. In addition, FOXM1 expression correlated with GLI1, SHh and PTCH1 expression in cancer tissues. These findings confirmed the participation of FOXM1 and the Hh signaling pathway in cervical cancer. Furthermore, the finding that FOXM1 may be a downstream target gene of the Hh signaling pathway in cervical cancer provides a potential novel diagnostic and therapeutic target for cervical cancer.

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“…The widely used hedgehog inhibitor cyclopamine belongs to a group of plant-derived alkaloids, first identified for their teratogenic activity in sheep [ 1 ]. Cyclopamine acts through direct binding to Smo, therefore, inhibiting the downstream canonical Hh signaling pathway [ 69 ]. It has also been shown to inhibit the non-canonical Akt pathway, although the precise mechanism for this is not clear [ 3 , 70 ].…”

Section: Potential Therapeutic Targeting Of the Hedgehog-signalingmentioning

confidence: 99%

The Potential Role of Hedgehog Signaling in the Luminal/Basal Phenotype of Breast Epithelia and in Breast Cancer Invasion and Metastasis

Flemban¹,

Qualtrough²

2015

Cancers

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The epithelium of the lactiferous ducts in the breast is comprised of luminal epithelial cells and underlying basal myoepithelial cells. The regulation of cell fate and transit of cells between these two cell types remains poorly understood. This relationship becomes of greater importance when studying the subtypes of epithelial breast carcinoma, which are categorized according to their expression of luminal or basal markers. The epithelial mesenchymal transition (EMT) is a pivotal event in tumor invasion. It is important to understand mechanisms that regulate this process, which bears relation to the normal dynamic of epithelial/basal phenotype regulation in the mammary gland. Understanding this process could provide answers for the regulation of EMT in breast cancer, and thereby identify potential targets for therapy. Evidence points towards a role for hedgehog signaling in breast tissue homeostasis and also in mammary neoplasia. This review examines our current understanding of role of the hedgehog-signaling (Hh) pathway in breast epithelial cells both during breast development and homeostasis and to assess the potential misappropriation of Hh signals in breast neoplasia, cancer stem cells and tumor metastasis via EMT.

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Combination of Cyclopamine and Tamoxifen Promotes Survival and Migration of MCF-7 Breast Cancer Cells – Interaction of Hedgehog-Gli and Estrogen Receptor Signaling Pathways

Cited by 22 publications

References 53 publications

Non-canonical Hedgehog signaling activation in ovarian borderline tumors and ovarian carcinomas

Non-canonical Hedgehog signaling activation in ovarian borderline tumors and ovarian carcinomas

Association between FOXM1 and hedgehog signaling pathway in human cervical carcinoma by tissue microarray analysis

The Potential Role of Hedgehog Signaling in the Luminal/Basal Phenotype of Breast Epithelia and in Breast Cancer Invasion and Metastasis

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