G0S2 as a Master Regulator of the Local Estrogenic Environment During Breast Cancer Progression and Antiestrogen Therapy
Abstract
The overarching challenges are: (1) Identify what drives breast cancer growth; determine how to stop; and (2) Eliminate the mortality associated with metastatic breast cancer. Antiestrogen therapy in the form of drugs, including tamoxifen and aromatase inhibitors like anastrozole, exemestane, and letrozole, are a mainstay for the treatment of estrogen receptor positive (ER+) breast cancer. However, many women, especially those with advances disease, become resistant to these therapies and die from their disease. We found through unbiased approaches that a protein called G0S2 can alter the levels of estrogen in breast cancer cells by directly altering the machinery the makes and degrades estradiol, the most potent estrogen. We also showed that those patients that have high levels of G0S2 have a lower rate of recurrence after antiestrogen therapy. Our objective is to provide further evidence that G0S2 modulates the estrogen biosynthetic pathway to suppress the growth of ER+ breast cancer, and that the loss of G0S2 that is typically seen in breast cancer compared to normal breast tissue promotes ER+ breast cancer by increasing the tumor levels of estradiol. We also want to understand how G0S2 alters the estrogen biosynthesis pathway. To uncover new alternative targeted therapies for breast cancers that fail antiestrogen therapy, it is vital to further understand the mechanisms of recurrence. Our discovery that G0S2 expression is frequently repressed in human breast cancer, and that this repression is associated with recurrence and alteration in estradiol bioavailability, may have major impact in predicting recurrence and mechanisms of sensitivity and resistance to antiestrogen therapy. If our hypothesis is proven correct, we can obtain additional funding, including breakthrough 3 and 4 awards, to bring G0S2 into the clinic as a biomarker of antiestrogen therapy response and to develop drugs that will induce G0S2 levels in breast cancer patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310530
Entities
People
- Michael Spinella
Organizations
- United States Army
- University of Illinois Urbana–Champaign