Estradiol induces bone osteolysis in triple-negative breast cancer via its membrane-associated receptor ERα36

D Joshua Cohen; Cydney D Dennis; Jingyao Deng; Barbara D Boyan; Zvi Schwartz

doi:10.1093/jbmrpl/ziae041

Estradiol induces bone osteolysis in triple-negative breast cancer via its membrane-associated receptor ERα36

JBMR Plus. 2024 Mar 26;8(5):ziae041. doi: 10.1093/jbmrpl/ziae041. eCollection 2024 May.

Authors

D Joshua Cohen¹, Cydney D Dennis¹, Jingyao Deng¹, Barbara D Boyan^{1

2}, Zvi Schwartz^{1

3}

Affiliations

¹ Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA 23284, United States.
² Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, United States.
³ Department of Periodontics, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229United States.

Abstract

Triple-negative breast cancer (TNBC) is thought to be an estradiol-independent, hormone therapy-resistant cancer because of lack of estrogen receptor alpha 66 (ERα66). We identified a membrane-bound splice variant, ERα36, in TNBC cells that responds to estrogen (E₂) and may contribute to bone osteolysis. We demonstrated that the MDA-MB-231 TNBC cell line, which expresses ERα36 similarly to MCF7 cells, is responsive to E₂, forming osteolytic tumors in vivo. MDA-MB-231 cells activate osteoclasts in a paracrine manner. Conditioned media (CM) from MDA-MB-231 cells treated with bovine serum albumin-bound E₂ (E₂-BSA) increased activation of human osteoclast precursor cells; this was blocked by addition of anti-ERα36 antibody to the MDA-MB-231 cultures. Osteoclast activation and bone resorption genes were elevated in RAW 264.7 murine macrophages following treatment with E₂-BSA-stimulated MDA-MB-231 CM. E₂ and E₂-BSA increased phospholipase C (PLC) and protein kinase C (PKC) activity in MDA-MB-231 cells. To examine the role of ERα36 signaling in bone osteolysis in TNBC, we used our bone-cancer interface mouse model in female athymic homozygous Foxn1^nu mice. Mice with MDA-MB-231 tumors and treated with tamoxifen (TAM), E₂, or TAM/E₂ exhibited increased osteolysis, cortical bone breakdown, pathologic fracture, and tumor volume; the combined E₂/TAM group also had reduced bone volume. These results suggest that E₂ increased osteolytic lesions in TNBC through a membrane-mediated PLC/PKC pathway involving ERα36, which was enhanced by TAM, demonstrating the role of ERα36 and its membrane-associated signaling pathway in bone tumors. This work suggests that ERα36 may be a potential therapeutic target in patients with TNBC.

Keywords: ERα36; SERMs; bone resorption; bone–tumor interface; cross-talk; estrogen; osteoclasts; osteolysis; tumor–induced bone disease.