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 anchorage-independent 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.
Highlights
The homeobox gene superfamily encodes for transcription factors that play important roles in development (1)
We provide evidence that the Six[1] homeoprotein plays a causal role in mammary tumor initiation, leading to highly aggressive mammary tumors in vivo
Because an increase in DNA double strand breaks (DSB) can promote genomic instability, leading to increased chromosomal breaks and translocations, we examined these cells for such gross chromosomal abnormalities by spectral karyotype (SKY) analysis (Fig. 2B)
Summary
The homeobox gene superfamily encodes for transcription factors that play important roles in development (1). As ‘‘master regulators’’ of development, homeoproteins control diverse cellular processes by regulating the expression of many downstream target genes. It is typical for an individual homeoprotein to confer pleiotropic effects on cell behavior. Six[1] promotes entrance into and progression through S phase and attenuates the DNA damage–induced G2 cell cycle checkpoint (14, 15). Together, these properties of Six[1] may contribute to its role in tumorigenesis
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