Changes in Transport into the Nucleus in Breast Cancer

Institution: Scripps Research Institute
Investigator(s): Deborah Sweet, Ph.D. -
Award Cycle: 1995 (Cycle I) Grant #: 1FB-0489 Award: $5,047
Award Type: Postdoctoral Fellowship
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease

Final Report (1995)
The aim of the research described in this proposal is to characterize the relationship between changes in movement of proteins between the nucleus and cytoplasm and the development of breast cancer. Exchange of proteins between the nucleus and cytoplasm occurs continuously and at a rapid rate, and is a fundamental aspect of normal cellular activity. It is also an important element of cell growth regulation, particularly for transmission of growth signals such as steroid hormones to the genome to produce changes in gene expression that alter the growth rate. Characterization of differences in the transport capacity of normal breast cells compared to those at different stages of conversion to a cancerous state will provide new insights into a previously unexplored aspect of the development of breast cancer. Improved understanding of these changes will provide additional information about the characteristics of breast tumors and could be used to enhance hormone-based strategies.

Transport of proteins from the cytoplasm to the nucleus across the nuclear envelope, i.e., nuclear protein import, is a signal- and energy-dependent process that requires the activity of both nuclear envelope-associated and cytoplasmic factors. The nuclear import capacity of cells has been shown to vary depending on their growth state: rapidly growing cells have significantly higher nuclear import rates than cells that are not actively growing. The proposed research will characterize differences in the nuclear import capacity of human breast cell lines representing normal, proliferating and malignant tumor cells, with the aim of identifying the changes that occur during the development of cancer.

Mislocalization of steroid hormone receptors is a feature of some forms of breast cancer, so this study will also include a focus on the nuclear import of these receptors. It has recently become clear that steroid hormone receptors move continuously between the nucleus, where they affect gene expression, and the cytoplasm. Specific or general changes in the nuclear import pathway could therefore have significant effects on receptor localization within the cell and be a contributory factor in the development of cancer.

In the last few years, rapid progress has been made in understanding the molecular mechanism of nuclear protein import. Differences observed between the various cell types will therefore be investigated in more detail to determine whether they can be attributed to known transport factors, to better understand the molecular basis of breast cancer.