Preclinical and clinical studies of breast cancer prevention with transdermal anti- progesterone agents

: we continue to test low dose ulipristal acetate (UPA), in combination with the anti-inflammatory drug celecoxib for prevention of Brca1 deficient mammary tumorigenesis. Recently, Howell et al. reported that UPA 5mg treatment in healthy premenopausal women at high risk for breast cancer significantly decreased 1) cell proliferation (ki67 LI), particularly more effective to luminal progenitor (LP) cells; 2) downregulated expression of cell cycles and extracellular matrix (ECM)-related genes and proteins; 3) ECM remodeling (34 martisome signature) is likely mediated by fibroblasts (PDGFRA+) and LP cells (RANK+) (SABCS 2022 Poster# P1-10-01). These results are consistent with our results that UPA significantly delay and prevent Brca1-deficient mouse mammary tumorigenesis1, supporting our hypothesis to test low dose UPA. Although the clinical development of UPA 5mg has been halted due to rare idiosyncratic liver toxicity at the post marketing stage 2,3 our study will provide important information regarding the tumor-protective potential of PR antagonism with low-dose UPA (HED 5mg daily P.O) in BRCA1-deficient mammary tumorigenesis; and whether such a tumor protective effect can be augmented by combining this with standard dose of Celecoxib, a nonsteroidal anti-inflammatory drug (the rationale detailed in our 2021 application).