There is a large population of breast cancer high-risk women who are also on antipsychotics in the U.S. Antiestrogen treatment is the only FDA-approved therapy for preventing breast cancer, but it requires prolonged and continuous treatment. Consequently, women who are still cancer-free often decline antiestrogen prevention or discontinue the treatment prematurely. The overall goal of this proposal is to test a novel concept in breast cancer prevention for women on antipsychotic dopamine antagonists. Our preliminary data suggest the following hypothesis: Dopamine-antagonizing neuroleptics activate STAT5 and STAT3 in preexistent early precancerous lesions in the breast. These two STAT proteins suppress the apoptosis anticancer barrier in these early lesions and accelerate their progression to cancer. Consequently, intermittent treatment to block STAT5 and STAT3 activity can effectively prevent breast cancer in high- risk women on dopamine-antagonizing neuroleptics.
Three aims are as follows:
Specific Aim 1. To determine whether in rodent models bearing mammary early lesions, dopamine-antagonizing neuroleptics activate STAT5 and STAT3 in these early lesions, suppress apoptosis, and accelerate progression to cancer.
Specific Aim 2. To determine whether in early lesion-bearing rodents on dopamine-antagonizing neuroleptics, genetic ablation of STAT5 and/or STAT3 restores apoptosis in these early lesions and slows the progression to cancer, and to discover the molecular mechanism by which neuroleptic treatment activates STAT3.
Specific Aim 3. To determine whether in early lesion-bearing rodents on dopamine-antagonizing neuroleptics, short- term or intermittent treatment to block STAT5/3 activity prevents mammary tumors.

Public Health Relevance

There is a large population of breast cancer high risk women on antipsychotics in the U.S. The overall goal of this proposal is to test a novel concept in breast cancer prevention for women on antipsychotics. We hypothesis antipsychotics use sensitizes high-risk women on antipsychotics for chemoprevention by intermittent treatment to suppress STAT proteins that are activated in early precancerous lesions in these women.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA205594-03
Application #
9623326
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Dunn, Barbara K
Project Start
2017-02-01
Project End
2022-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030