Six1 Overexpression in Mammary Cells Induces Genomic Instability and Is Sufficient for Malignant Transformation

Abstract

Homeoproteins are transcription factors that act as master regulators of development and are frequently dysregulated in cancers. During embryogenesis, the Six1 homeoprotein is essential for the expansion of precursor cell populations that give rise to muscle and kidney, among other organs. Six1 overexpression is observed in numerous cancers, resulting in increased proliferation, survival, and metastasis. Here, we investigate whether Six1 can play a causal role in mammary tumor initiation. We show that Six1 overexpression in MCF12A mammary epithelial cells promotes multiple properties associated with malignant transformation, including increased proliferation, genomic instability, and anchorageindependent growth. We further show that this transformation is dependent on up-regulation of its transcriptional target, cyclin A1, which is normally expressed in the embryonic mammary gland but dramatically reduced in the adult gland. Six1-transformed MCF12A cells are tumorigenic in nude mice, forming aggressive tumors that are locally invasive and exhibit peritumoral lymphovascular invasion. In human breast carcinomas, expression of Six1 and cyclin A1 mRNA correlate strongly with each other (P < 0.0001), and expression of Six1 and cyclin A1 each correlate with Ki67, a marker of proliferation (P < 0.0001 and P = 0.014, respectively). Together, our data indicate that Six1 overexpression is sufficient for malignant transformation of immortalized, nontumorigenic mammary epithelial cells, and suggest that the mechanism of this transformation involves inappropriate reexpression of cyclin A1 in the adult mammary gland. [Cancer Res 2008;68(7):2204-13]

Six1 expression is associated with a poor prognosis in patients with glioma

“…processes, such as proliferation, apoptosis, migration, and invasion (9,(21)(22)(23). The Six1 homeoprotein is a member of the Six family of homeodomain transcription factors and has been found to be upregulated in multiple cancers, including breast cancer (12,20,24), rhabdomyosarcomas (18,25,26), hepatocellular carcinomas (19), ovarian cancer (13) and Wilms' tumors (17).…”

“…In addition to the involvement of Six1 in the early development of organs, the gene is often misexpressed in diverse tumors, including breast cancer (12), ovarian cancer (13,14), cervical cancer (15,16), Wilms' tumors (17), rhabdomyosarcomas (18) and hepatocellular carcinoma (19). Additionally, the misexpression of Six1 in cancer may induce developmental programs out of context, contributing to tumor onset and progression (20,21).…”

SIX1 promotes epithelial–mesenchymal transition in colorectal cancer through ZEB1 activation

“…The SIX1 homeoprotein has been implicated in both tumor initiation and tumor progression in many human cancers (Ford et al, 1998;Yu et al, 2004;Ng et al, 2006;Behbakht et al, 2007;Coletta et al, 2008;McCoy et al, 2009;Micalizzi et al, 2009), although the molecular mechanisms of SIX1 activity and SIX1 targets are not fully understood. SIX1 is known to contribute to tumor formation and metastatic progression by regulating multiple activities of cancer cells, such as genome stability (Coletta et al, 2008), responsiveness to apoptotic stimuli (Behbakht et al, 2007), cell proliferation (Coletta et al, 2004) and epithelial differentiation (Micalizzi et al, 2009).…”

“…SIX1 is known to contribute to tumor formation and metastatic progression by regulating multiple activities of cancer cells, such as genome stability (Coletta et al, 2008), responsiveness to apoptotic stimuli (Behbakht et al, 2007), cell proliferation (Coletta et al, 2004) and epithelial differentiation (Micalizzi et al, 2009). Recently, several studies provide evidence that SIX1 induces EMT to promote tumor development (McCoy et al, 2009) and activate transforming growth factor-b (TGF-b) signaling in mammary cells (Micalizzi et al, 2009;Micalizzi et al, 2010b).…”

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

“…It is important to note that Six1 overexpression has been strongly associated with aggressive, metastatic cancers and poor prognosis (Coletta et al, 2004;Yu et al, 2004;Behbakht et al, 2007). Recently, Six1 overexpression in immortalized mammary epithelial cells has been shown to induce transformation, leading to highly aggressive and invasive tumors in nude mice (Coletta et al, 2008). Despite Six1's important role during development and frequent deregulation in a large number of neoplasms, surprisingly little is known about its regulation.…”