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Rabbit uteroglobin is the founder member of a family of mammalian proteins that has expanded to more than 20 members within the last few years. All members are small, secretory, rarely glycosylated dimeric proteins with unclear physiological functions and are mainly expressed in mucosal tissues. A phylogenetic analysis shows that the family can be grouped into five subfamilies, A to E. Subfamily A contains rabbit uteroglobin and its orthologues from various species; most of these have been described to form antiparallel homodimers via two intermolecular disulfide bonds. All other subfamily members contain a third conserved cysteine and, from existing biochemical data, it can be predicted that a member of subfamily B or C will likely form heterodimers with a partner from subfamily E or D, respectively. Besides the mentioned cysteines, only one central lysine is conserved in all family members. In the known uteroglobin structures, this lysine forms an exposed salt bridge with an aspartate side chain, which is conserved in almost all sequences. Using radiation hybrid mapping and P1 clone analysis and utilizing data from the human genome project, we show that all known five human family members (Clara cell 10-kDa protein, lipophilins A and B, lacryglobin, mammaglobin) and a new member, we call lymphoglobin, are localized on chromosome 11q12.2 in a dense cluster spanning not more than approximately 400 kbp.

It has been suggested that mammaglobin may be a useful marker for breast cancer clinical research. Studies investigating the detection of mRNA by RT-PCR from circulating carcinoma cells in the peripheral blood of breast cancer patients have shown that mammaglobin is a highly specific marker and correlates with several prognostic factors, such as lymph node involvement. We aimed to detect cell-free mammaglobin mRNA in the plasma of breast cancer patients and to investigate whether it can be used as a marker for diagnosis of breast cancer.

The mammaglobin gene encodes a 10-kDa glycoprotein that is distantly related to a family of proteins that includes rat estramustine binding protein (EMBP)/prostatein and human Clara cell 10-kDa protein (CC10)/uteroglobin. Among normal adult tissues, mammaglobin mRNA expression has been detected only in the mammary gland. As an initial step to determine mammaglobin's clinical utility as a breast tumor marker, we evaluated the frequency and specificity with which mammaglobin expression could be detected in primary breast tumors, metastatic breast tumors, and breast tumor cells present in the peripheral circulation. Approximately 80% of all primary and metastatic breast tumors examined were strongly immunopositive for mammaglobin protein, and staining was independent of tumor grade. Among peripheral stem cell collections from breast cancer patients, mammaglobin mRNA could be detected in 60% of cases. Recent work has identified the secreted mammaglobin protein in the sera of some breast cancer patients using both Western blot and ELISA. This study demonstrates that the detection of mammaglobin protein and mRNA in clinical samples may be a useful marker for primary, metastatic, and occult breast cancer.