James N. Ingle, MD

Last year, three BCRF-funded projects under Dr. Ingle's direction were being conducted at the Mayo Clinic:
1) One project is identifying ways to tell a woman whether or not a certain type of BRCA1 or BRCA2 mutation (called a "missense" mutation) is associated with an increased risk of breast cancer. This accomplished by studying how these mutations track with cancer in families and by complementing this with laboratory studies. Thus far, 150 mutations have been defined as neutral (lacking clinical significance) and 20 mutations have been defined as deleterious (cancer predisposing).
2) The researchers have shown in human breast cancer cell lines and in models that exposure to estrogen can increase the levels of the aurora A protein, which in known to be over-expressed in approximately 80% of all breast cancers. Aurora A acts to stabilize a major protein involved in the mechanics of cell proliferation and therefore may serve to increase the rate of cell proliferation in a manner that promotes chromosomal instability and leads to malignancy.
3) A third project examined variants of estrogen receptor (ER) £\ called ER beta and ER beta-cx and showed that the ER£\ and ER£] regulate unique patterns of genes but the ER£]cx variant had no activity. The scientists also found that non-responsive breast cancer cells still maintained the functional ER signaling pathway suggesting that the loss of responsiveness to hormonal treatment is probably due to changes in target genes. This information should lead to better hormonal therapy for patients by understanding the roles these receptors play in breast cancer growth and resistance to treatment.

In the coming year, the Ingle team will focus on a single project, focused on tamoxifen, one of the most important treatments available for women with breast cancer and one that has received approval from the Food and Drug Administration for use in the full spectrum of breast cancer from metastatic disease to women at high risk of developing breast cancer. Although it has been used for over 30 years, new information has recently become available regarding the way it is metabolized by patients, which can vary tremendously.

Results of numerous recent studies in the laboratory and in patients indicate that a specific metabolite of tamoxifen called endoxifen may be the most important determinant of how much benefit women receive from taking tamoxifen. The research to be conducted will examine the effects of endoxifen and compare it with those of a different metabolite that has been used in breast cancer research in the past (called 4-hydroxy-tamoxifen or 4-HT). This project aims to examine the differences in the molecular actions of endoxifen and 4-HT by determining differences in the gene expression patterns elicited by these compounds in breast cancer cells. The researchers will also determine the effects of endoxifen and 4HT on breast cancer cell proliferation and cell death.

These studies will be performed in cells that express estrogen receptor alpha or estrogen receptor betaƒz as well as breast cancer cells that either respond to, or are resistant to, hormone therapy. All of these breast cancer cell lines have recently been developed in the Mayo Clinic laboratory. The studies will reveal whether endoxifen has unique actions relative to 4HT and will further our knowledge regarding the molecular basis for the development of tumors that are resistant to hormone therapy. The ultimate goal is to improve hormonal therapy for women with breast cancer.

Mid-Year Progress Report:
The research underway will examine the effects of endoxifen and compare it with those of a different metabolite, 4-hydroxytamoxifen, which has been the main focus in breast cancer research for the past 2 decades, and fulvestrant, an important drug, called a pure anti-estrogen, in the treatment of breast cancer. The purpose of these studies is to determine the actions and potency of endoxifen and gain a better understanding of what occurs in breast cancer cells when a breast cancer becomes resistant to tamoxifen therapy. In the three months since this project started initial findings point to potentially important findings and these are being replicated. The knowledge gained will be applied to translational studies using tissue samples from women treated with tamoxifen.

Bio:
Dr. Ingle is Professor of Oncology and Foust Professor in Mayo Clinic College of Medicine. He has been chair of the Mayo Breast Cancer Clinical Trials Committee since 1982 and is the leader of breast cancer research in the Mayo Clinic Comprehensive Cancer Center serving as Program Co-Leader of the Women's Cancer Program. Dr. Ingle is the Director of the Mayo Clinic Breast Cancer Specialized Program of Research Excellence. He was chair of the Breast Committee of the North Central Cancer Treatment Group for 22 years, assuming the position of senior advisor to that committee in 1999.

His primary interests are in clinical trials of new therapeutic approaches in breast cancer, with an emphasis on endocrine therapy, and translational research. Other active research involves the study of the biology of endocrine sensitivity, genes and pathways related to breast cancer, and immunotherapy. He has over 200 peer-reviewed publications. He has served on numerous national and international bodies such as the NIH (1990) and St. Gallen (2003, 2005) Consensus Conference Panels on early breast cancer.