2. Academic Validation
  3. Z-Endoxifen prevents aggressive mammary cancers in mice by inhibiting cell proliferation and creating a tumor suppressive microenvironment

Z-Endoxifen prevents aggressive mammary cancers in mice by inhibiting cell proliferation and creating a tumor suppressive microenvironment

  • Biomed Pharmacother. 2023 Jun:162:114607. doi: 10.1016/j.biopha.2023.114607.
Oukseub Lee 1,  Minhua Wang 2,  Omid Hosseini 2,  Maarten C Bosland 3,  Miguel Muzzio 4,  Irene Helenowski 5,  Seema A Khan 6
Affiliations

Affiliations

  • 1 Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. Electronic address: o-lee@northwestern.edu.
  • 2 Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  • 3 Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA.
  • 4 Analytical Chemistry Division, Illinois Institute of Technology Research Institute, Chicago, IL, USA.
  • 5 Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  • 6 Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. Electronic address: s-khan2@northwestern.edu.
PMID: 37001185 DOI: 10.1016/j.biopha.2023.114607
Abstract

Aggressive Estrogen Receptor (ER) positive breast Cancer is frequently tamoxifen-resistant; alternative endocrine approaches exist for therapy, but not for prevention, particularly in premenopausal women. We examined the efficacy of the selective ER modulator (Z-endoxifen) as monotherapy and in combination with the selective Progesterone Receptor modulators (onapristone and ulipristal acetate) in the tamoxifen-insensitive C3(1)/SV40TAg mouse mammary tumorigenesis model. Unlike tamoxifen at human equivalent dose (HED) 101 mg/day, endoxifen at HED 24 mg/day significantly increased latency and reduced tumor growth relative to untreated controls. Ulipristal acetate (UPA) at HED 81 mg/day also significantly increased latency however failed to inhibit tumor growth, while onapristone (HED 98 mg/day) had no tumor prevention efficacy in this model. Addition of UPA to endoxifen did not enhance preventive efficacy over endoxifen alone. The expression of genes associated with cell cycle, cell proliferation and extracellular matrix remodeling was similarly repressed by endoxifen and UPA however only endoxifen significantly downregulated prominent genes associated with poor prognosis (Col11a1, Il17b, Pdgfa, Tnfrsf11a). Our results indicate that endoxifen can prevent breast cancers, even when tamoxifen-resistant, through its role in favorable tissue remodeling and immunomodulation.

Keywords

C3(1)TAg; Endoxifen; Tamoxifen; Tumorigenesis; Ulipristal acetate.

Figures
Products