As an MD/PhD student, I enter the lab after completing the first 2 years of medical school and graduate school coursework. Although I have not had extensive clinical experiences yet, I enter my research lab with a unique medical education. As a future physician-scientist, my goal is to become comfortable and successful in transitioning between the clinic and the lab bench. Entry into my thesis lab is the first of many transitions that I foresee. In the future, I hope to attain a position where I have the opportunity to integrate the creative, but methodical approach of the lab with the compassion and diagnostic manner of the clinic. With each new transition, I hope to bring a new perspective to my work and become more adept at incorporating both fields. To reach this goal, I will not settle for mediocrity, but will strive to immerse myself in my project and learn all that I can as a researcher.

My research project focuses on the Six1 homeodomain protein. This protein acts as a transcription factor and is expressed during the development of multiple organs, including the mammary gland. In development, Six1 is a critical regulator of cell proliferation, survival, and migration. Although most adult tissues have low or absent levels of Six1, in breast cancer 50% of primary and 90% of metastatic lesions overexpress Six1. Six1 overexpression in a human nontumorigenic mammary epithelial cell line induces tumor formation in nude mice, and the tumors observed are highly aggressive and invasive. Furthermore, preliminary data using Six1 overexpression in mouse models indicate that Six1 overexpression can lead to mammary tumor formation and to metastasis. Given these data, we suggest that Six1 plays multiple roles in tumorigenesis, influencing both tumor initiation and progression. However, the mechanism by which Six1 contributes to tumor initiation and progression is unknown.

While no two cancers are exactly alike, similar properties are altered in cancer cells compared to normal cells. For instance, cancer cells no longer require growth signals to proliferate and are no longer responsive to growth inhibitory signals. In addition, cancer cells will eventually acquire the ability to invade and metastasize. Based on Six1's functions during normal development, inappropriate expression of Six1 in the adult mammary gland may reinstitute developmental programs that are pro-proliferative and pro-migratory. Work in our lab has demonstrated that Six1 overexpression in a human mammary epithelial cell line leads to increased proliferation and migration, as well as to tumor formation in nude mice. It is my goal to characterize the molecular mechanisms of Six1's pro-proliferative and pro-migratory effects and determine whether these mechanisms also contribute to the pro-tumorigenic activity of Six1. Identification of the molecular mechanisms responsible for the tumorigenic properties induced by Six1 will begin to elucidate the role of Six1 in tumor formation and progression. Discovering the target genes necessary for Six1-mediated tumorigenesis will not only contribute to the study of the role of Six1 in breast cancer, but will also provide potential drug targets for breast cancers overexpressing Six1.

We believe that Six1 is an excellent candidate for drug targeting for three reasons. First, Six1 plays a role at multiple stages of tumorigenesis, influencing proliferation, transformation, and tumor metastasis, and as such, targeting it should inactivate the tumor at multiple fronts. Second, as Six1 is a developmental gene, it is expressed primarily in cancer cells and not in most normal adult tissue, thus targeting it would minimize drug toxicity. Finally, as 50% of patients with primary breast cancer and 90% with metastatic lesions overexpress Six1, targeting this gene, or genes in its pathway, should be a realistic therapy for a very large percentage of breast cancer cases. Understanding the mechanism of Six1-mediated tumor formation will be essential in realizing the potential of Six1 as a drug target. While this work is still some years from the clinic, when combined with the development of mouse models in our lab, it will lay the foundation for testing the utility of targeting the Six1 pathway for anti-breast cancer therapy in vivo.