Gene Amplification Is a Mechanism of <i>Six1</i> Overexpression in Breast Cancer

Reichenberger, Kelly J.; Coletta, Ricardo D.; Schulte, Aline P.; Varella‐Garcia, Marileila; Ford, Heide L.

doi:10.1158/0008-5472.can-04-4286

Cited by 103 publications

(93 citation statements)

References 51 publications

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“…Aberrant Six1 overexpression in numerous human cancers has been shown to result in increased proliferation, tumor cell survival, drug resistance and metastasis (Coletta et al, 2004;Yu et al, 2004;Reichenberger et al, 2005;Behbakht et al, 2007). Our results showing lower levels of miR-185 and increased levels of Six1 expression in multiple human cancers indicate that miR-185 may be a critical regulator of Six1 pro-proliferative role and that loss of miR-185 expression may be one of the important events in Six1-mediated tumorigenesis.…”

Section: Discussionmentioning

confidence: 52%

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: 52%

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

et al. 2010

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“…Cyclin A1 is a downstream effector for Six1 in breast cancer where overexpression of Six1 promotes cyclin A1 expression and subsequently increases cell proliferation and progression (Coletta et al, 2004). Gene amplification of Six1 is a probable mechanism contributing to tumorigenesis in breast cancer (Reichenberger et al, 2005). Overexpression of Six1 in RMS cells can boost their pulmonary metastasis potential, whereas downregulation of Six1 suppresses their metastatic ability (Yu et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Clinicopathological significance of homeoprotein Six1 in hepatocellular carcinoma

Man

et al. 2006

Br J Cancer

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Tumour recurrence and metastases of hepatocellular carcinoma (HCC) after hepatectomy are the major obstacles of long-term survival. The present study investigated the clinicopathological significance of a possible metastasis regulator Six1 in HCC patients who were undergone hepatectomy. Seventy-two pairs of RNA and 103 pairs of protein from tumour and adjacent nontumour liver tissues of HCC patients were examined. About 85 and 60% of HCC tumour tissues were found to overexpress Six1 mRNA and protein, respectively, compared with nontumour liver tissues. No Six1 protein was detected in HCC nontumour liver tissues and normal liver tissues. Increased Six1 protein expression in HCC patients was significantly correlated with pathologic tumour-nodemetastasis (pTNM) stage (P ¼ 0.002), venous infiltration (P ¼ 0.004) and poor overall survival (P ¼ 0.0423). We concluded that Six1 is frequently overexpressed in HCC patients and elevated Six1 protein in HCC patients may be an indication of advanced stage and poor overall survival after hepatectomy.

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“…However, SIX1 expression is low in adult tissues, and aberrant expression of the SIX1 gene in adult tissue may contribute to carcinogenesis (10). 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).…”

Section: Introductionmentioning

confidence: 99%

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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Gene Amplification Is a Mechanism of Six1 Overexpression in Breast Cancer

Cited by 103 publications

References 51 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

Clinicopathological significance of homeoprotein Six1 in hepatocellular carcinoma

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

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