Our lab is interested in the genetic pathways involved in breast cancer malignancy. To pursue these interests, we use genomic approaches to compare and contrast tumor-derived cell lines, primary tumors from patients, and tumors from mouse models. We use a combination of cell culture experiments and in vivo genetics to directly test how perturbations in the pathways we identify from our genomic studies influence the mechanisms of tumor progression and metastasis. Our goals are to improve breast cancer diagnosis and reveal potential therapeutic targets through an improved understanding of molecular and cellular biology of tumors.

 

 

Our current research is focused on the role of tight junction complexes in regulating epithelial to mesenchymal transition (EMT) and invasive cell behavior. EMT describes processes that cause epithelial cells, which normally form sheets of interconnected cells, to dissemble their intercellular junctions, lose apical-basal polarity, and acquire mesenchymal characteristics, such as increased motility. There are many parallels to these changes observed in tumors progressing to invasive and metastatic forms, so elucidating EMT molecular pathways provides a useful framework for studying cancer progression mechanisms. EMT pathways are reused in numerous developmental stages and in adult tissues during wound healing, and as we often observe in biology, important pathways that mediate vital processes are also highly conserved across evolution. Many key EMT genes studied in mammalian cells, like TWIST, SNAIL, and SLUG, were first identified as fruit fly mutations. Comparative studies of human cell biology and experimental model systems are complementary approaches that accelerate our discovery efforts.

 

Understanding EMT mechanisms is not just an academic exercise, but has direct relevance to cancer biology. We and others have found that neoplastic epithelial cells have the ability to co-opt normal EMT pathways to acquire mesenchymal characteristics, such as increased motility and invasiveness. These are important properties since distant metastasis is often the cause of cancer-associated morbidity. In addition, cell morphology is evaluated in tumor staging as an indication of cellular differentiation, although the concept of EMT is not used in current clinical classification schemes. Furthermore, recent studies indicate EMT induction may also confer stem cell properties to mammary epithelial cells, which may contribute to their intractability to current therapies. Thus, elucidating the pathways of cancer-associated EMTs may yield useful diagnostic biomarkers and reveal new opportunities for therapeutic interventions. Our efforts are especially relevant to a novel breast cancer molecular subtype we call Claudin-Low tumors that we discovered in a cross-species comparison of mouse and human breast cancers. These tumors show morphological and molecular features characteristic of EMT. Ongoing studies in the lab focus on characterizing a mouse model we engineered that mimics many salient features of human Claudin-Low tumors, further characterizing primary tumors from patients, and exploring the molecular basis that uniquely distinguishes these tumors from other breast cancer subtypes.