Novel strategies for therapeutic intervention of breast and ovarian cancer

Breast and ovarian cancer are projected to account for over 55,000 deaths in 2008, with breast cancer being the second most common cancer diagnosed in women. In combination with improved prevention and diagnosis, more targeted, effective, and less toxic treatments are also needed.  The studies being carried out by Dr. Brugge’s laboratory are exploring fundamental biological questions of epithelial cell biology while concomitantly employing insights gained from these investigations to help understand the pathology of tumors such as breast and ovarian cancer. The study of basic cellular mechanisms such as gene expression, cell death, cell migration, mammary gland development, and oxidative stress is unveiling key aspects of normal cellular function that can become dysregulated in the neoplastic state. Consequently, elucidation of these processes at the molecular level may yield a wealth of useful information for efforts directed at anticancer pharmacologic intervention. 
 

Dr. Brugge’s current research is focused on understanding the morphogenetic and differentiation mechanisms that characterize epithelial tissues such as the mammary gland, as well as the basic cellular processes that are integral to normal and pathological conditions. Moreover, the lab is investigating the oncogenic signaling mechanisms that mediate the development and progression of breast and ovarian cancer, as well as drug resistance.

The lab continues to explore the molecular mechanisms that mediate basic cellular mechanisms underlying control of  cell proliferation, differentiation, migration, invasion,  death processes such as apoptosis, anoikis, and entosis (i.e., non-apoptotic cell death by engulfment within a cell), as well as oxidative stress responses, and metabolic consequences of matrix deprivation. These key phenomena are essential cellular processes of normal and transformed cells. Most of this work is performed in the context of 3D cultures in which the epithelial cells are able to organize into structures resembling natural glandular tissues.

At the molecular level, these research studies have honed in on specific proteins that appear to be intimately involved in the cellular mechanisms described above. These projects include functional studies of particular proteins that can promote oncogenesis, such as Yap, support apoptosis, such as the mitochondrial protein Bim, or directly modulate gene expression at the transcription level, such as PDEF (prostate-derived ETS factor).

Importantly, these investigations involve the study of cellular and molecular activities that function in normal cells but can go awry in transformed cells, thus revealing insights into tumor biology.

Dr. Brugge joined the faculty of the Department of Cell Biology at Harvard Medical School in July 1997 and became the Chair of this department in 2004. The recipient of numerous awards for her scientific accomplishments, she has been elected to the American Academy of Arts and Sciences, the National Academy of Sciences and the Institute of Medicine.

Dr. Brugge’s research has focused on epithelial cell biology, encompassing both normal physiology and pathological conditions such as breast cancer. Her approach emphasizes the use of 3-dimensional culture models, which more closely mimic the in vivo state. These spherical lumen-containing cell clusters have been employed to study the molecular basis of various processes, including epithelial cell morphogenesis, apoptosis, and migration. Her recent high-profile findings pertaining to breast epithelial cell migration employed a high throughput siRNA technology coupled with rigorous confirmatory experiments to screen for genes that modulate the ability of human breast cancer cells to repair a wound. This study uncovered 42 genes that heretofore were not linked to cell migration, thus adding significantly to our knowledge base for this important cellular phenomenon. In conjunction with the publication of these findings, the lab has publicly released an interactive database that facilitates easy access to the wealth of data generated from this large scale siRNA study, thus setting a new standard for public access to laboratory data.

Other recent studies have explored the molecular mechanisms associated with mammary gland morphogenesis and lumen formation, a complex process that involves apoptosis and anoikis (i.e., cell detachment-induced apoptosis). The lab has investigated the role of various proteins in these cell death mechanisms, and identified Bmf and Bim as two molecules important for regulating cell death and lumen formation in the mammary gland. Moreover, Bmf expression is regulated by oncogenic signaling pathways, demonstrating an intriguing link between normal tissue morphogenesis and tumorigenesis. 
 

Biological Mechanisms and Pathways

• Anoikis •
• Antioxidant •
• Apoptosis •
• Cancer metabolism •
• Cancer stem cell •
• Cell death •
• Cell differentiation •
• Cell invasion •
• Cell migration •
• Development •
• Entosis •
• Epithelial •
• Epithelial cell •
• Extracellular matrix •
• Lumen formation •
• Morphogenesis •
• Oncogene •
• Signal transduction
•  

Cancer

• Apoptosis •
• Breast cancer •
• test
•  

Disease Mechanisms

• Breast cancer •
• Epithelial tumor •
• Ovarian cancer
•  

Research Tools and Instrumentation

• 3-dimensional basement membrane cell cultures •
• 3-dimensional basement membrane cell cultures
•  

Therapeutics

• Antioxidant
•