Targeting of Tumor-Promoting Galectins in Breast Cancer

Institution: Sidney Kimmel Cancer Center
Investigator(s): Margaret Huflejt, Ph.D. -
Award Cycle: 2001 (Cycle VII) Grant #: 7IB-0039 Award: $182,500
Award Type: IDEA
Research Priorities
Detection, Prognosis and Treatment>Imaging, Biomarkers, and Molecular Pathology: improving detection and diagnosis



Initial Award Abstract (2001)
We are studying a group of proteins called galectins in breast cancer diagnosis, prognosis, and treatment. These proteins are present in breast cancer cells and tissues, and absent in the normal breast cells and tissues. Galectins are present inside the cells, but they can also be released into the tumor-surrounding tissues and contribute to the tumor cell adhesion and metastasis. In addition, these external galectins might suppress the immune response, and block apoptosis (programmed cell death) of cancer cells. Previously, we have observed specific pattern of high local induction, or 'hot spots', of one of these tumor-promoting proteins known as galectin-4, in benign biopsy tissues of patients who progressed to malignancy within 1-5 years.

Certain small molecules composed of sugars and amino acids called glycoamines are highly concentrated in sera of cancer patients, and absent in sera of healthy individuals. However, it is unknown how early in the progression of breast disease these compounds appear in sera. It is likely that some of these glycoamines are natural inhibitors of galectins. Small non-toxic synthetic glycoamines have been produced, and we have shown that one of these compounds inhibits galectin-1, and restores the ability of immune cells to produce cancer cell-killing molecules. Taken together, our data show that galectins might both help to predict breast disease progression, and be targets for therapy.

In this project we will expand our studies of galectin-4 and galectin-1 in human breast cancer. We plan to study the expression patterns of these proteins in tissues of patients with the benign disease and with broad spectrum of breast cancers. We will also use advanced analytical techniques allowing detection of glycoamines in these patients' sera. During our studies, we will collaborate with clinicians to match the data on tissue galectin-4 and -1 amounts and the serum levels of glycoamines, with the disease status of the individual patients. Our aim is to develop a rapid, sensitive, inexpensive and non-invasive method for screening of patients early in the disease for risk of progression. The combined goal is to determine whether galectins 'hot spots' in breast biopsy samples are evidence of a predisposition to tumor progression, and whether serum glycoamine structures can provide new information leading towards development of synthetic glycoamine analogs as a non-toxic way of blocking tumor-promoting activities of galectins, such as the immunosuppression observed in breast cancer patients.

Since galectins are extracellular, they are more accessible to therapeutic intervention than genes and proteins inside of cancer cells. We believe that further investigations of biology of galectins and glycoamines are warranted to establish these molecules both as important clinical markers of breast cancer and as candidates for translational developments.


Final Report (2003)
Notes: This grant was extended 1-yr to complete then aims and funding. The CBCRP awarded the PI an additional grant in 2003 to study galectin inhibitors as a means to overcome immune tolerance to breast cancer.

We studied a group of proteins, called galectins, that are present in large quantities in breast cancer cells and tissues, and are absent in the normal breast cells and tissues. Galectins are present inside the cells, but they can also be released into the tumor-surrounding tissues and contribute to tumor cell adhesion and metastasis. In addition, we hypothesize these external galectins might suppress the immune response, and protect cancer cells from death. We found a specific pattern of high local induction, or 'hot spots', of one of these tumor-promoting proteins known as galectin-4, in benign biopsies of patients who progressed to malignancy within 1-5 years. This suggested that the presence of galectin-4 in benign tissues indicates high risk of progression to malignancy.

In this project we have further expanded our studies of galectin-4 in human breast cancer. First, we have developed monoclonal anti-galectin-4 specific antibodies, and we are now in a process of selecting the antibody suitable for clinical diagnostic/prognostic marker. We have the ability to study patients who initially presented with benign disease and to monitor their rate of progression to malignancy. The newly developed monoclonal antibody will be used with this large-population study in which galectin-4 expression patterns in benign, pre-malignant and malignant breast disease are matched with patients' responses to treatments, time to tumor progression and survival. Next, we have developed advanced analytical techniques allowing detection of glycoamines in patients' sera, and we continue collecting information about the correlation between serum glycoamine appearances, galectin-4 tissue expression profiles, and the treatment outcomes. Finally, we have generated two individual carbohydrate-binding domains of human galectin-4 as recombinant proteins which were then used to identify small non-toxic compounds that specifically block galectin-4 activity, and these compounds are candidates as anti-cancer drugs.

This study has provided the foundation for a translational clinical research project aimed at the development of a diagnosis - based treatment: Sensitive, inexpensive and non-invasive serum-based method would identify patients with early signs of breast disease. Patients showing early induction of glycoamines indicating tissue presence of tumor-promoting galectins would be potential candidates for preventive and/or anti-cancer treatments including non-toxic, selective galectin inhibitors.