Novel Mechanisms Whereby p27 Drives Tumor Progression in PI3K-Activated Cancers
Abstract
This grant addresses the overarching challenges to: (1) Identify what drives breast cancer growth; determine how to stop it and (2) Identify why some breast cancers become metastatic. Death from breast cancer is rarely if ever caused by the first tumor that appears in the breast tissue itself. Rather, breast cancer kills affected individuals because cancer cells evolve to have the ability to go into the bone, liver, and lung and even the brain to form new metastatic tumors that ultimately interfere with normal organ function. We are starting to understand that the cells within the cancer are not uniform in their malignant behavior. Some are more treatment-resistant, can escape the first site of their growth in the breast and metastasize, that is, migrate in the body to new organ sites where they cause havoc with normal tissue. The most aggressive cancer cells that act like pioneers to explore new tissue sites have undergone switches in the pattern of genes they express. One important transformation permitting cells to move and relocate is called the epithelial to mesenchymal transformation or EMT. Cells that have undergone the EMT conversion are very resistant to chemo- and radiation therapies and metastasize readily in mouse models of breast cancer. Our treatments, while effective in reducing tumor size, do not seem to hit the most aggressive cells -- those with the ability to serve as tumor refreshers or initiating stem cells that relocate and grow at new sites to form metastasis. This grant addresses how p27, which normally puts the “brakes” on cancer growth, becomes deregulated and loses its growth inhibitory action and becomes a driver of metastasis. p27 is a small protein expressed in every cell of the body. One of its normal roles is to inhibit the cell’s progression through its growth cycle and prevent the cell from doubling its DNA and dividing into two cells. p27 is often reduced or lost in cancer cells, providing them with a growth advantage since they have “lost their brakes.” However, p27 is rarely completely lost from cancer cells. We are beginning to appreciate that this is because p27 can be changed by interacting with important growth signaling pathways that get hyperactivated in cancer cells. p27 goes from being a “good” inhibitor of growth to being bent out of shape, taking up bad company, and driving aggressive cancer growth. Our earlier work showed the growth inhibitory action of p27 is subverted in cancers by a molecular switch called phosphorylation that changes its shape and the pattern of proteins that it can interact with and talk to. p27 goes from being a growth inhibitor to a cancer metastasis driver. When the HER2 gene is amplified, as it is in about 30% of breast cancers (those that can respond to Herceptin), an important signaling pathway, the PI3K pathway, gets hyperactivated, leading to changes in p27 that promote aggressive growth and drive cancer metastasis. The PI3K pathway is also activated in many other non-HER2 amplified cancers -- about 60% in total. Unfortunately, newly developed PI3K inhibitor drugs have been relatively disappointing as single drug treatment regimens for breast cancer. Our grant may identify how other targeted therapies might be combined with PI3K inhibitors to inhibit cancer stem cells and prevent or reduced the size of cancer metastasis. We have some new insights into how the PI3K pathway changes p27. Work planned in this grant will help understand how a molecular switch caused by p27 phosphorylation alters its shape to permit it to bind and assemble molecular complexes to change the expression of genes that turn on metastatic ability. These broad changes in genes expressed lead to new cell behaviors including greater motility and greater potential for the cancer cell to invade into surrounding tissues, survive in this abnormal environment, and get into the blood stream to relocate to new tissues in the body (like the liver, lung, and bone)
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710456
Entities
People
- Joyce M Slingerland
Organizations
- United States Army
- University of Miami