Principal Investigator

Yi
Li
Awardee Organization

Baylor College Of Medicine
United States

Fiscal Year
2021
Activity Code
R01
Project End Date

Ruxolitinib for Preventing Breast Cancer in Women on Neuroleptics

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 highrisk 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, shortterm or intermittent treatment to block STAT5/3 activity prevents mammary tumors.

Publications

  • Bu W, Liu Z, Jiang W, Nagi C, Huang S, Edwards DP, Jo E, Mo Q, Creighton CJ, Hilsenbeck SG, Leavitt AD, Lewis MT, Wong STC, Li Y. Mammary Precancerous Stem and Non-Stem Cells Evolve into Cancers of Distinct Subtypes. Cancer research. 2019 Jan 1;79(1):61-71. Epub 2018 Nov 6. PMID: 30401712
  • Johnston AN, Bu W, Hein S, Garcia S, Camacho L, Xue L, Qin L, Nagi C, Hilsenbeck SG, Kapali J, Podsypanina K, Nangia J, Li Y. Hyperprolactinemia-inducing antipsychotics increase breast cancer risk by activating JAK-STAT5 in precancerous lesions. Breast cancer research : BCR. 2018 May 19;20(1):42. PMID: 29778097
  • Bu W, Li Y. Intraductal Injection of Lentivirus Vectors for Stably Introducing Genes into Rat Mammary Epithelial Cells in Vivo. Journal of mammary gland biology and neoplasia. 2020 Dec;25(4):389-396. Epub 2020 Nov 9. PMID: 33165800
  • Young A, Bu W, Jiang W, Ku A, Kapali J, Dhamne S, Qin L, Hilsenbeck SG, Du YN, Li Y. Targeting the Pro-survival Protein BCL-2 to Prevent Breast Cancer. Cancer prevention research (Philadelphia, Pa.). 2022 Jan;15(1):3-10. Epub 2021 Oct 19. PMID: 34667127