Characterization of hAG-2 and Its Role in Breast Cancer

Institution: Stanford University
Investigator(s): Devon Thompson, M.Sc., Ph.D. -
Award Cycle: 1999 (Cycle V) Grant #: 5KB-0083 Award: $166,465
Award Type: New Investigator Awards
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease



Initial Award Abstract (1999)
All breast tumors, from either biopsies or excisions, are examined for the presence of a protein called estrogen receptor. This helps clinicians to evaluate the prognosis and most suitable course of treatment for the patient. Many tumors that contain estrogen receptor (ER+) prove to be responsive to hormone therapy, whereas those tumors that do not contain estrogen receptor (ER-) respond poorly to hormone therapy. Overall, ER+ breast cancers are a better target for hormone therapy, often using the anti-estrogen drug tamoxifen.

We have discovered a new gene, called hAG-2, that appears to be operative only in those breast tumors that are ER+. We are examining many aspects of hAG-2 in efforts to understand how and why it is present, together with ER, in breast cancer tumors. This is important, because even though ER+ breast cancers respond to hormone therapy, often these therapies fail or resistance develops. Thus, more information, targets for therapy, and potential clinical biomarkers are needed for women with ER+ breast cancers.

The overall objective of this research project is to delineate the biological role of hAG-2 and to ascertain the significance of hAG-2 as a marker for mammary and breast tumor differentiation. Our specific aims include, (1) examining clinical breast tumor samples for hAG-2 amounts, particularly correlated with tumor grade, ER status, and stage, (2) studying hAG-2 expression during mammary development in the mouse, and (3) producing hAG-2 as a recombinant protein and generating antibodies for detailed cell localization and other studies. More information on factors that control hAG-2 in breast cancer will clarify the significance of ER as the most important clinical marker of the disease and focus (and failure) of current therapy. The association of hAG-2 with ER implicates it as a key player in breast tumor biology.

We anticipate that hAG-2 will emerge as an important factor for breast cancer tumor development, and perhaps mammary development. Ultimately, knowledge at the molecular level will be pivotal to designing intelligent cancer treatment strategies.


Final Report (2001)
Note: This grant was resigned in February 2001, so Dr. Thompson could accept another position.

Breast tumors that are removed for biopsy or resection are evaluated for several parameters. This examination assists clinicians in determining the prognosis and most suitable course of treatment for the patient. One marker that is particularly useful is estrogen receptor (ER) because tumors that contain this protein (ER+) often respond well to anti estrogen drug treatment. We have discovered a new gene, called hAG 2 that appears to be operative only in those breast tumors that are ER+. This research is studying hAG 2 in efforts to understand how and why it is present, together with ER, in breast cancer tumors.

The aims of this research project were to delineate the biological role of hAG 2 and to ascertain the significance of hAG 2 as a marker for differentiation. Specific aim 1: Examination of 29 breast tumor specimens showed that the levels of hAG 2 correlate with the levels of ER in 79% of the samples. The remaining 21% of the tumors that did not follow this pattern, and these tumors did not have any common pathological features that would distinguish them. Overall, the levels the hAG2 are clearly higher (p <0.03) in breast tumors that also exhibit high levels of estrogen receptor. Specific aim 2: Preliminary in situ hybridization experiments showed that hAG 2 is present in the nose, tail, foot, mammary gland and rib regions of the 1 7 day gestation mouse embryo. To date no differences in the levels of hAG 2 have been observed in the adult mouse mammary gland during the stages differentiation. However, a comparison between normal human breast tissue and human breast carcinomas demonstrated that hAG 2 expression is significantly higher in tumors (p g.0009) Specific aim 3: Highly soluble recombinant hAG 2 was produced and purified. This was used to generate a highly specific and reactive antibody against the hAG 2 protein. Preliminary experiments have shown that this antibody will be an extremely valuable tool for studying the biology of hAG 2. Initial experiments in breast cancer cell lines indicated that hAG 2 protein levels were increased following estradiol treatment. This is of interest because it implies that hAG 2 may be a hormone responsive gene.

Future research should be directed at further examining the role of hAG 2 during embryonic development, mammary gland differentiation and cell cycle. Efforts were focused on determining if hAG 2 is secreted and these studies were incomplete. It would be of value identify the target or receptor for hAG 2. The association of hAG 2 with ER implicates it as a key player in breast tumor biology. More information on factors that control hAG 2 in breast cancer will help clarify the significance of ER as an important clinical marker of the disease. We anticipate that hAG 2 will emerge as an important factor for breast cancer tumor development, and perhaps mammary development. Ultimately, knowledge at the molecular level will be pivotal to designing intelligent cancer treatment strategies.

PDZKI and GREB1 are estrogen-regulated genes expressed in hormone-responsive breast cancer.
Periodical:Cancer Research
Index Medicus: Cancer Res
Authors: Ghosh MG, Thompson DA, and Weigel RJ
Yr: 2000 Vol: 60 Nbr: 22 Abs: Pg:6367-6375