TGF-Beta Receptor Signaling and Breast Cancer

Institution: Lawrence Berkeley National Laboratory
Investigator(s): Kunxin Luo, Ph.D. -
Award Cycle: 1998 (Cycle IV) Grant #: 4KB-0151 Award: $362,691
Award Type: New Investigator Awards
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease

Initial Award Abstract (1998)
Breast cancer cells differ from normal breast cells in two important aspects: 1) the growth of normal breast cells is tightly regulated, while breast cancer cells can grow in an uncontrolled manner; 2) in response to environmental stimuli, normal breast cells can stop growing and perform special functions such as producing milk, a process called differentiation. Cancer cells, in contrast, no longer respond to environmental signals and fail to perform breast-specific functions. The growth and differentiation of normal breast cells are two intimately related processes that are regulated by growth factors. Disruption of this regulatory program will result in formation of breast cancer. Therefore, in order to understand how breast cancer develops, we need to examine how growth and differentiation of normal breast cells are regulated, and how this regulation is disrupted in breast cancer cells.

One of the growth factors that play an important role in the regulation of breast cell differentiation is transforming growth factor- or TGF. TGF can inhibit the growth of normal breast cells and early stage breast cancer cells. It also triggers differentiation of normal breast cells. TGF exerts these effects by binding to the surface of cells and by attaching to the TGF receptor molecules. Activated TGF receptors then send signals into the cells to inhibit growth and trigger differentiation. It is yet not clear how these signals are transmitted inside the cells. The goal of this proposal is therefore to study how TGF regulates normal breast cell differentiation, and to investigate the role of TGF receptor molecules in this process. We will use a cell culture system that mimics the three-dimensional breast environment inside our body. In this system, normal breast cells can be manipulated to differentiate to various degrees, while breast cancer cells fail to differentiate. Thus, this system can recapitulate the major difference between normal and cancerous breast cells. The effects of TGF on normal breast cell differentiation will be examined in this culture system. The role of TGF receptors in mediating TGF generated signals during differentiation of normal breast cells will also be investigated. These receptors will also be introduced into malignant breast cancer cells to examine whether they can restore the ability of these cancer cells to be growth inhibited by TGF. If successful, this should represent a new strategy for breast cancer therapy. Taken together, these studies should allow a better understanding of the pathogenesis of breast cancer and may contribute to better diagnosis and treatment of breast cancer.

Final Report (2001)
Transforming growth factor- (TGF) plays an important role in regulation of breast cell function. It inhibits the growth of normal breast cells, but not metastatic breast cancer cells. The goal of this proposal is to study how TGF regulates normal breast cell maturation (differentiation). The specific aims are: 1) Determine the effects of TGF on normal breast cell differentiation. 2) Determine the role of TGF receptors during normal breast cell differentiation. 3) Determine the role of TGF receptors in breast cancer progression.

Smad proteins are critical mediators of TGF signaling. We recently identified two cancer proteins located in the nucleus of the cell, Ski and SnoN, as negative regulators of Smad proteins and TGF signaling. Ski and SnoN interact with the Smad proteins on a TGF-responsive DNA element and block their abilities to activate TGF target genes. More importantly, overproduction of Ski or SnoN blocked TGF-induced growth inhibition. Thus, these two oncoproteins provide us with a powerful tool to repress TGF signaling.

To determine whether elevated level of SnoN leads to breast carcinogenesis, we first examined the levels of SnoN production in various normal and cancerous mammary epithelial cells. SnoN protein was produced at a very low or undetectable level in normal mammary epithelial cells, but at high levels in early, non-invasive tumor cells and at moderate levels in metastatic and invasive cell lines. Thus, a high level of SnoN production correlates with oncogenic transformation, supporting the model that SnoN may play a role in carcinogenesis. Furthermore, these results, although preliminary, may suggest that SnoN may function at the early stage of carcinogenesis. In future experiments, we will first examine the activity of Smad proteins in these mammary epithelial cells to determine whether it correlates with the level of SnoN production. By overproducing these two proteins in normal breast cells, we will examine whether blocking of TGF signaling interferes with normal mammary epithelial cell differentiation and results in breast cancer formation.

Negative Feedback regulation of TGFB signaling by the SnoN oncoprotein
Index Medicus: Science
Authors: Stroschein, S.L., Wang, W., Zhou, S., Zhou, Q., Luo, K.
Yr: 1999 Vol: 286 Nbr: 5440 Abs: Pg:771-4