Why do 70% of Breast Cancers Metastasize to Bone?

Institution: The Burnham Institute for Medical Research
Investigator(s): Jose Millan, Ph.D. -
Award Cycle: 1996 (Cycle II) Grant #: 2IB-0151 Award: $97,407
Award Type: IDEA
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease



Initial Award Abstract (1996)
One of the most important determinations that a physician must make when examining a patient afflicted by breast cancer is whether the tumor is confined to the breast or, instead, has already spread to other regions of the body. The process of cancer spreading is called metastasis, and once a cancer has progressed to the stage of metastatic disease, the probability that a patient will be treated successfully and cured are greatly reduced. The bone tissue is the preferred site of metastasis in patients with breast cancer.

In spite of the high frequency of bone metastases, the mechanisms that favor the skeleton as a preferred site for breast cancer spreading are completely unknown. The work proposed in this application aims at identifying molecules that may be providing this homing signal to the cancer cells. We will achieve this by using a molecular trick whereby billions of distinct protein sequences are examined for their ability to identify bone as a preferred target. We will identify and establish the building blocks of these small proteins and confirm that they are able to recognize bone specifically.

If this strategy is successful, subsequent experiments, beyond the scope of this proposal, will enable us to characterize the actual molecules present on the surface of breast cancer cells to understand, in detail, the mechanism of homing and metastasis to bone.


Final Report (1997)
One of the most important determinations that a physician must make when examining a patient afflicted by cancer is whether the tumor is confined to the organ of origin or it has already spread to other regions of the body. The process of cancer spreading is called metastasis, and once a cancer has progressed to the stage of metastatic disease, the probability that a patient will be treated successfully and cured are greatly reduced. The bone tissue is the preferred site of metastasis in patients with breast cancer and approximately 70% of breast cancer patients show bone metastases at the time of death. There is no information available about what molecules may be participating in the metastatic process in breast cancer. In this IDEA proposal, we hypothesize that breast cancer cells that are circulating in the blood stream initiate the metastatic process by making landfall onto the surface of endothelial cells in the bone marrow mediated by ligand/receptor-like interactions. Our experiments have been designed to test this hypothesis as well as to identify molecules that can compete with this initial step that may serve as novel therapeutics useful in early intervention and prevention of metastatic breast cancer disease.

While receptor molecules and their ligands can be rather large molecules, the site of interaction and of specificity can be restricted to just a few amino acids. We have used phage display peptides libraries to search for peptides, which may adhere preferentially to endothelial cells in the bone marrow. With this methodology phage libraries expressing billions of peptides sequences can be screened in a single experiment and the structure of the binding site(s) identified by simple microbiological and recombinant DNA techniques. The sequence of some of the peptides that we have uncovered indeed show homology to proteins that participate in ligand/receptor interactions, such as opioid binding protein, coagulation factor VIII, mouse homologue of notch protein, and entactin, giving confidence to the use of this methodology.

We now must proceed to confirm that the homing of these identified peptides is restricted to bone endothelial cells and to assess whether these peptide sequences exist in the context of a metastatic breast cancer molecule or cDNA and to identify the actual receptors on the surface of endothelial cells. These peptide sequences may also be effective in blocking metastasis and thus become useful novel molecular therapeutic compounds. The phage-displayed peptides may be useful in targeting vectors designed for gene therapy of bone diseases.