Heide L. Ford, PhD

2011-2012 BCRF Project: The Six1/Eya complex plays a critical role in the onset and progression of breast cancers but has never before been clinically targeted. Six1 expression is low or undetectable in normal breast tissue but it is over-expressed in 50% of primary breast tumors and 90% of metastatic lesions. Dr. Ford's team has demonstrated in laboratory models that the over-expression of Six1 results in enhanced proliferation, transformation, increased tumor volume, and metastasis. Importantly, RNA interference against Six1 decreases cancer cell proliferation and metastases in breast cancer models. The Eya proteins are coactivators of Six1 that seem to "switch" the Six1 transcriptional complex from a repressor to an activator complex. The Six1-Eya interaction is essential for proliferation during embryonic development, and both Six1 and Eya2 have been independently implicated in the same types of cancer. Furthermore, coordinate over-expression of Six1 and Eya2 significantly correlates with a dramatically shortened time to relapse and metastasis, and with shortened survival in breast cancers. These findings suggest that Eya and Six1 cooperate to stimulate breast tumorigenesis and progression. Importantly, recent evidence demonstrates that Eya protein's phosphatase activity is critical for breast cancer metastasis.

Based on the above observations, Dr. Ford's team therefore has formed the hypothesis that the Six1/Eya complex is an ideal drug target whose inactivation will inhibit breast tumor cell proliferation and metastasis. Because Six1 and Eya2 are embryonic genes with very limited expression in the adult, inhibitors of their expression/activity are likely to have limited side effects. In 2011-2012, the researchers aim to identify small molecules that inhibit the Eya phosphatase activity and small molecules that inhibit the Six1/Eya interaction. The accomplishment of these goals will further enhance the establishment of Six1/Eya complex as a new drug target.

Mid-year Progress: Since July 2011, Dr. Ford and colleagues have made significant progress towards identifying inhibitors that target the Six1/Eya complex, and they are beginning to characterize how these inhibitors work. They have identified a class of compounds that target the enzymatic activity of Eya, which allows Eya to remove phosphate groups from proteins. This enzymatic activity is known to be critical for the ability of Eya to induce metastasis, and Dr. Ford's data show that the compounds she and colleagues have identified can enter the cell and inhibit properties mediated by Eya. In addition, these researchers have determined the structure of Six1 bound to Eya, and have begun to use the structural information to identify compounds that are expected to inhibit metastasis by breaking up the interaction between the two proteins. Indeed, they have shown that disrupting this interaction, using a genetic means, significantly inhibits the ability of Six1 to mediate both tumor initiation and metastasis. In the coming year, they will synthesize more potent compounds that can be used to test whether they are efficacious in laboratory models of tumor onset and progression.

Bio:
Dr. Ford has been working on the role of the Six1 homeobox gene in tumorigenesis and metastasis since the late 1990s and has spent many years elucidating the mechanisms by which Six1 contributes to tumorigenicity and metastasis. Dr. Ford's main focus has been on understanding the numerous molecular mechanisms by which Six1 alters cell proliferation, cell survival, the epithelial to mesenchymal transition, and cancer stem cell characteristics, leading to its ability to induce both tumorigenesis and metastasis.

Dr. Ford's laboratory was the first to observe an overexpression of the developmental regulator Six1 in any cancer, and since then her group as well as many others have implicated it in both initiation and progression of many different tumor types. In addition, in the past few years Dr. Ford's team has dedicated much effort to understanding the role of the Six1 cofactor Eya, in mediating Six1-induced tumorigenic and metastatic phenotypes.

Dr. Ford's laboratory has published numerous papers (in journals such as Journal of Clinical Investigations, Proceedings of the National Academy of Science, Cancer Research, and others) that revolve around the role of the Six1 homeobox gene in tumorigenicity and metastasis. Many of their publications include work in transgenic, knockout, or xenograft models. In addition, Dr. Ford's recent focus has been almost entirely on the metastatic process, which is a significant theme in the project that is funded by BCRF in 2011-2012, as this research team would like to develop drugs that inhibit this process.

Based on the above observations, Dr. Ford's team therefore has formed the hypothesis that the Six1/Eya complex is an ideal drug target whose inactivation will inhibit breast tumor cell proliferation and metastasis. Because Six1 and Eya2 are embryonic genes with very limited expression in the adult, inhibitors of their expression/activity are likely to have limited side effects. In 2011-2012, the researchers aim to identify small molecules that inhibit the Eya phosphatase activity and small molecules that inhibit the Six1/Eya interaction. The accomplishment of these goals will further enhance the establishment of Six1/Eya complex as a new drug target.