Defining a role for the homeoprotein Six1 in EMT and mammary tumorigenesis

Radisky, Derek C.

doi:10.1172/jci40555

Cited by 22 publications

(22 citation statements)

References 20 publications

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“…Similarly, reduced levels of miR-185 resulting in altered expression of Six1 in differentiated tissues may in part lead to the reinitiation of developmental cell proliferative pathways in Six1-overexpressing adult tumors. In agreement with this, Six1-induced mammary epithelial to mesenchymal transition has been associated with increased mammary stem/progenitor cell self-renewal and tumorigenesis (McCoy et al, 2009;Radisky, 2009). Furthermore, Six1 transcriptional target cyclin A1, which is normally expressed in embryonic but not in differentiated mammary gland, when reactivated because of uncontrolled Six1 expression, results in increased proliferation of breast cancer cells (Coletta et al, 2004).…”

Section: Discussionmentioning

confidence: 72%

MicroRNA-185 suppresses tumor growth and progression by targeting the Six1 oncogene in human cancers

et al. 2010

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Homeobox genes encode transcription factors that are essential for normal development and are often dysregulated in cancers. The molecular mechanisms that cause their misregulation in cancers are largely unknown. In this study, we investigate the mechanism by which the Six1 homeobox protein, which has a crucial role during development, is frequently deregulated in several poor outcome, aggressive, metastatic adult human cancers, including breast cancer, ovarian cancer, hepatocellular carcinoma and pediatric malignancies such as rhabdomyosarcoma and Wilms' tumor. Our results reveal that miRNA-185 translationally represses Six1 by binding to its 3 0 -untranslated region. Analyses of ovarian cancers, pediatric renal tumors and multiple breast cancer cell lines showed decreased miR-185 expression, paralleling an increase in Six1 levels. Further investigation revealed that miR-185 impedes anchorage-independent growth and cell migration, in addition to suppressing tumor growth in vivo, implicating it to be a potent tumor suppressor. Our results indicate that miR-185 mediates its tumor suppressor function by regulating cell-cycle proteins and Six1 transcriptional targets c-myc and cyclin A1. Furthermore, we show that miR-185 sensitizes Six1-overexpressing resistant cancer cells to apoptosis in general and tumor necrosis factor-related apoptosisinducing ligand (TRAIL)-mediated apoptosis in particular. Together, our findings suggest that the altered expression of the novel tumor suppressor miR-185 may be one of the central events that leads to dysregulation of oncogenic protein Six1 in human cancers.

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Section: Discussionmentioning

confidence: 72%

MicroRNA-185 suppresses tumor growth and progression by targeting the Six1 oncogene in human cancers

et al. 2010

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“…The present study further investigated the molecular pathways involved in SIX1-induced cancer progression. Previous reports indicated that SIX1 could induce EMT, which is closely associated with cancer cell invasion and metastasis (16,17). Previous studies indicated that SIX1 could induce ERK activation (34).…”

Section: Discussionmentioning

confidence: 97%

“…Although studies have indicated that numerous oncogenes in endometrial carcinoma promote cancer progression, novel markers to predict aggressive phenotypes are urgently required. The upregulation of SIX1 expression has been reported in human gynecological cancers, including breast, cervical and ovarian carcinoma, where it leads to increased proliferation and metastasis (13)(14)(15)17). One study reported that SIX1 was aberrantly upregulated in human colorectal cancer and promoted epithelial-mesenchymal transition via zinc finger E-box binding homeobox 1 activation (26).…”

Section: Discussionmentioning

confidence: 99%

“…SIX1 was found to be overexpressed in human breast, cervical, ovarian and pancreatic cancers and associated with a poor patient survival (11)(12)(13)(14)(15). SIX1 overexpression promotes cancer cell survival and epithelial to mesenchymal transition (EMT) (16,17). Overall, these findings suggest that SIX1 is an important oncoprotein for the development of cancer.…”

Section: Introductionmentioning

confidence: 97%

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SIX1 is overexpressed in endometrial carcinoma and promotes the malignant behavior of cancer cells through ERK and AKT signaling

Xin

Yang

2016

Oncology Letters

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Abstract. The sineoculis homeobox homolog 1 (SIX1) protein has been found to be important for cancer progression. However, its biological role in human endometrial carcinomas remains unexplored. The potential mechanism of SIX1-induced cancer progression remains unclear. In the present study, SIX1 protein expression was examined in 84 cases of endometrial carcinoma tissues using immunohistochemisty, and SIX1 was found to be overexpressed in 51.1% (43/84) of cervical cancer cells. Small interfering RNA (siRNA) knockdown of SIX1 was also performed in Ishikawa cells with high endogenous SIX1 expression, and SIX1 was overexpressed in the HEC1B cell line with low endogenous expression. SIX1 overexpression promoted cell growth rate and colony formation ability, whereas SIX1 depletion inhibited cell growth and colony formation. Further analysis showed that SIX1 knockdown downregulated, and SIX1 overexpression upregulated, cyclin D1, cyclin E, phosphorylated (p-)extracellular signal-regulated kinase (ERK), and p-protein kinase B (AKT) expression. The ERK inhibitor, U0126, and AKT inhibitor treatments blocked the effect of SIX1 on proliferation. In conclusion, the present study found that SIX1 overexpression promotes cancer cell growth in endometrial carcinoma, possibly through ERK-and AKT-mediated pathways.

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“…Some of these non‐canonical HOX genes have been identified in expression screens of breast cancer as frequently overexpressed and having direct effects on the regulation of cell proliferation or neoplastic potential. These include SIX1 , a member of the SIX homeotic gene family for which an oncogenic mechanism has been identified and that has frequently been characterized as overexpressed in human breast cancer . Likewise, other HOX ‐associated genes, not part of the four conserved HOX clusters, include BP1 and BMI1 both of which have also been implicated in the neoplastic phenotype in human breast cancer as have their HOX‐associated TALE protein cofactors .…”

Section: Introductionmentioning

confidence: 99%

Characterization ofHOXgene expression in canine mammary tumour cell lines from spontaneous tumours

DeInnocentes

Perry

Graff

et al. 2013

Vet Comparative Oncology

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Spatial/temporal controls of development are regulated by the homeotic (HOX) gene complex and require integration with oncogenes and tumour suppressors regulating cell cycle exit. Spontaneously derived neoplastic canine mammary carcinoma cell models were investigated to determine if HOX expression profiles were associated with neoplasia as HOX genes promote neoplastic potential in human cancers. Comparative assessment of human and canine breast cancer expression profiles revealed remarkable similarity for all four paralogous HOX gene clusters and several unlinked HOX genes. Five canine HOX genes were overexpressed with expression profiles consistent with oncogene-like character (HOXA1, HOXA13, HOXD4, HOXD9 and SIX1) and three HOX genes with underexpressed profiles (HOXA11, HOXC8 and HOXC9) were also identified as was an apparent nonsense mutation in HOXC6. This data, as well as a comparative analysis of similar data from human breast cancers suggested expression of selected HOX genes in canine mammary carcinoma could be contributing to the neoplastic phenotype.

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Defining a role for the homeoprotein Six1 in EMT and mammary tumorigenesis

Cited by 22 publications

References 20 publications

MicroRNA-185 suppresses tumor growth and progression by targeting the Six1 oncogene in human cancers

MicroRNA-185 suppresses tumor growth and progression by targeting the Six1 oncogene in human cancers

SIX1 is overexpressed in endometrial carcinoma and promotes the malignant behavior of cancer cells through ERK and AKT signaling

Characterization ofHOXgene expression in canine mammary tumour cell lines from spontaneous tumours

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