Regulatory Mechanisms for Growth & Motility in Breast Cancer

Institution: Scripps Research Institute
Investigator(s): Ulla Knaus, Ph.D. -
Award Cycle: 1995 (Cycle I) Grant #: 1IB-0491 Award: $82,900
Award Type: IDEA
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease



Initial Award Abstract (1995)
The development and progression of breast cancer is not well understood, but appears to involve changes in normal cellular regulatory mechanisms for growth and motility. Important parts of this regulation involve proteins known as kinases. Kinases activate or inhibit other proteins by attaching a chemical phosphate group. The formation of cancers has been shown to depend on at least one of these kinases, known as MAP kinase. Recent findings suggest additional kinase pathways may also play critical roles in the developing tumors and in their ability to spread to other parts of the body. Our studies will investigate a possible novel pathway through which breast cancer and other tumors might develop. Knowledge of this new mechanism will lead to greater understanding of the pathogenesis of breast cancer and will enable us to identify new biological markers able to predict the course of the cancer (prognostic indicators). Information obtained on regulation of the motile responses of breast cancers will allow us to develop means to reduce or prevent such spreading. This will be a tremendous benefit, since cancers of the breast can be readily accessed prior to their spread into additional organs.

Previous studies have shown that activity of the normal MAP kinase pathway is controlled by Ras protein and that Ras directly induces the formation of tumors in this way. Ras is one of a family of proteins which bind a signaling molecule known as GTP. Other GTP-binding proteins of the Ras family, termed Rac and CDC42, may control other equally important regulatory kinases. We have identified such kinases, which are called p21-activated kinases or Paks. Based on a variety of data, we hypothesize that the Rac GTP-binding protein, via its ability to modulate the activity of Pak, regulates another set of mammalian MAP kinases. These new MAP kinases are likely to be important for controlling breast cancer development and spreading (metastasis). Using molecular biological and biochemical approaches, we will first determine whether Pak controls one of these novel MAP kinase pathways. We will then proceed to identify the actual sequence of proteins that may be intermediate between Pak(s) and the novel MAP kinases. These findings will be evaluated directly in breast cancer-derived cells, assessing the effects of the novel pathway(s) on growth control and motility. The studies described here form the required initial steps to understand the molecular basis for breast cancer, ultimately and directly leading to a greater ability to intervene effectively in this disease.


Final Report (1996)
The development and progression of breast cancer appears to correlate with loss of regulatory control mechanisms for growth, differentiation and movement of cells. In order to understand the differences of cellular responses in normal and malignant breast tissue, it is important to obtain knowledge about the various regulatory pathways inside the cell. Major parts of this regulation involve proteins known as kinases. One of them, known as mitogen activated protein (MAP) kinase, has been already implicated in the formation of cancers. The goal of this project was the investigation of a possible novel regulatory pathway leading to the activation of MAP kinase-related protein kinases. Our studies have identified regulatory elements of two distinct protein kinase cascades that might affect tumor progression and ability to spread to other parts of the body. Knowledge of these new mechanisms allow us to now conduct further basic and clinical studies, which will lead to a greater understanding of the pathogenesis of breast cancer. This will enable us to identify new prognostic indicators to predict the course of cancer, particularly for cell migration, a prerequisite in metastasis.

Previous studies have shown that the activity of the MAP kinase pathway is controlled by Ras protein and that Ras directly induces the formation of tumors in this way. Ras is one of a family of proteins which bind a signaling molecule known as GTP. Other members of the GTP-binding family, termed Rac and Cdc42, are involved in alterations of the cellular shape which precede cell movement and migration through tissues. We have identified another set of MAP kinase-related protein kinases, termed SAPK, which are regulated by the action of the Rac/Cdc42 proteins. These pathways are composed of several protein kinases that are activated in sequence upon stimulation of the first kinase in the cascade. Our studies have established the protein kinase PAK as a direct partner protein for Rac-initiated events. We have shown that Rac/Cdc42 stimulate the SAPK pathway via their ability to modulate the activity of PAK. Preliminary evaluation of these findings in breast cancer-derived cells has revealed abnormal levels of PAK activity which indicates a loss of cellular control functions. These studies are initial steps to understand the molecular basis of breast cancer and have initiated further investigations to assess the effects of these novel pathways on growth control and motility.

Rho family GTPases regulate p38 mitogen-activated protein kinase through the downstream mediator Pak1
Periodical:Journal of Biological Chemistry
Index Medicus: J Biol Chem
Authors: Zhang S, Han J, Sells MA, Chernoff J, Knaus U, et al
Yr: 1995 Vol: 270 Nbr: 41 Abs: Pg:23934-23936