Glycoproteins are important biological copolymers that consist of both carbohydrate and protein and their degradation is catalyzed by hydrolytic enzymes.  One of the enzymes discovered in Dr. Aronson's laboratory termed "chitobiase" can also breakdown chitin, a pure carbohydrate polymer that helps form the molecular skeleton of both insects and crustacians.  Next to cellulose, chitin is the most abundant polysaccharide in the biosphere.  Both of these sugar polymers are long and flat, and this useful shape explains why nature has put them to extensive architectural use as "molecular boards".

A few years ago Dr. Aronson was analyzing the amino acid structure of the chitobiase enzyme they had discovered.  A computer search of the available database of protein and enzyme sequences revealed a large group of similar chitin-hydrolyzing enzymes.  What caught Aronson's eye, however, was an additional small set of structurally similar proteins that had one important change; these could not catalyze chitin digestion.  Among the almost 400 amino acids that make up a normal chitinase enzyme, nature had substituted for one crucial acid residue preventing these novel proteins from hydrolyzing the polysaccharide.  Little is known about the physiological function of these inactive chitinase-related proteins, but based on their structure they might likely bind a chitin-like polysaccharide or glycoprotein.  This molecular event would then help regulate various kinds of tissue remodeling and/or differentiation.  For example, one of these proteins only appears during wound repair in cartilage, while a second works during the earliest events of pregnancy when a newly fertilized ovum is implanted in the oviduct.   A third member of the chitinase-related protein group was discovered at Harvard University by scientists studying specific types of cancer cells from the mammary glands of mice.  The protein was named BRP39.  This abbreviation designates the tissue, time of occurrence, and size of the protein [B(breast)R(regression)P39(protein of 39,000 molecular weight)].  Not only does BRP39 appear in unique types of breast cancer cells, but these scientists also found it is expressed by the normal gland once the young mouse pups are weaned from their mother at the termination of breast feeding.  The latter physiological stage is called involution, a period when the breast not only stops producing the unique proteins and nutrients that form the mother's milk, but also the time in which the structure and function of the gland must revert back to the nonpregnant state.   Dr. Aronson's major initial goal is to determine the exact role that BRP39 has in this remarkable physiological process.  Other scientists have already reported many important biochemical details for the chitinase enzyme, and these data are being used to help us characterize similar molecular information about BRP39, especially the nature of its predicted chitin-binding domain.

Once it is learned how BRP39 acts during the normal process of mammary gland involution Aronson's research team plans to use this information to help reveal its behavior in the breast cancer cells where it was initially discovered. His initial hypothesis is that BRP39 acts normally as a protective signaling factor that determines which cells are to survive the drastic tissue remodeling that must occur during involution.  Thus, many breast epithelial cells which have been increased in number during pregnancy [in preparation for breast feeding] must now be destroyed.  These cells die by a precise programmed cell death pathway called "apoptosis", but most of the breast tissue remains viable, and we think BRP39 contributes to regulating which cells in the gland are to survive.  There is good evidence that BRP39 is secreted by breast epithelial cells, and therefore its signaling activity may involve either carbohydrate-containing molecules in the extracellular matrix or cell surface glycoproteins.

One could easily imagine that certain cancers could surreptitiously utilize the proposed normal  "protective signaling" by BRP39 in order to extend their own survival and thereby allow them to invade the organ and metastasize.  The type of breast cancer cells found to produce BRP39 is among the most dangerous.  This class overexpresses a growth factor receptor on their cell surfaces that is called HER-2/neu.  In human breast cancer patients, those who are positive for excess HER-2/neu protein have a negative prognosis for remission and survival.  Up to a third of breast cancers contain extra copies of the HER-2/neu gene, and biotech companies have recently developed tests to measure the level of HER-2/neu in breast cancer patients.  In late 1998, a new anti-HER-2/neu drug called Herceptin that attacks the growth factor receptor was approved by the FDA.  So far it has shown positive therapeutic results, especially when combined with a chemotherapeutic agent like Taxol.

Fig. 2 Proposed pathways by which BRP39 is induced (A) physiologically during involution of the breast; or (B) during breast cancers caused by overexpressed growth receptor HER/neu.  BRP39 upon binding either [I] to carbohydrate-containing molecules in the extracellular matrix (ECM) or [II] to cell surface glycoproteins may induce either protective effects on the mammary epithelial cells or metabolic changes that lead to cell destruction.

Dr. Aronson's research on BRP39 and the chitinases is a collaborative effort.  The computer remains a very crucial experimental tool for the project.  Dr. Aronson joined forces with Dr. Jeff Madura in the USA Chemistry Department who is an expert computational chemist able to predict protein structure using programs that involve advanced mathematics, physics and chemistry.  In January 1999, Dr. Madura relocated to Duquense University in Pittsburgh, but maintain a joint 5-year NIH grant to support these studies on BRP39 and chitinases.  Dr. Aronson's current  research studies are being performed by postdoctoral scientist Dr. Katja Reichert-Poeggeler, Brian (Zeke) Halloran and medical student Kerry Griffen.

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Revised: October 25, 1999