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HOXB5 Confers Tamoxifen Resistance in Breast Cancer Cells and Promotes Tumor Aggression and Progression

 Clara Yuri Kim  ;  Yu Cheon Kim  ;  Ji Hoon Oh  ;  Myoung Hee Kim 
 ANTICANCER RESEARCH, Vol.41(7) : 3409-3417, 2021-07 
Journal Title
Issue Date
Biomarkers, Tumor / genetics ; Breast Neoplasms / drug therapy* ; Breast Neoplasms / genetics* ; Breast Neoplasms / pathology ; Cell Line, Tumor ; Cell Movement / genetics* ; Disease Progression ; Drug Resistance, Neoplasm / genetics* ; ErbB Receptors / genetics ; Female ; Gene Expression Regulation, Neoplastic / genetics ; Homeodomain Proteins / genetics* ; Humans ; MCF-7 Cells ; Signal Transduction / genetics ; Stem Cells / pathology ; Tamoxifen / pharmacology
Breast cancer ; EGFR ; HOXB5 ; cancer stem cell ; endocrine-resistance
Background/aim: ER-positive breast cancer patients commonly undergo endocrine therapy with drugs such as tamoxifen. Despite tamoxifen being a highly effective drug, long-term treatment results in resistance in one-third of the patients. Although many explanations for the development of tamoxifen resistance have been put forward, a clearly defined underlying mechanism is still lacking.

Materials and methods: The expression level of HOXB5 was evaluated between MCF7 breast cancer cells and tamoxifen-resistant MCF7 (TAMR) cells by RT-PCR. Then, the effect of HOXB5 on invasion and migration abilities as well as on cancer stemness were investigated through 3D culture and spheroid formation assay.

Results: In this study, we provide evidence that HOXB5 is up-regulated in TAMR cells. EGFR is concurrently overexpressed, and the EGFR signaling cascade is activated, resulting in migratory and invasive phenotypes in TAMR cells compared to MCF7 cells. However, HOXB5 knockdown in TAMR cells resulted in the de-activation of the EGFR signaling pathway, less aggressive phenotypes and restoration of sensitivity to tamoxifen treatment. More interestingly, TAMR cells expressed higher levels of stem cell markers, and as a result, their enhanced stemness allowed for a better formation of spheroids than MCF7 cells. When HOXB5 was overexpressed in MCF7 cells, they were able to form a larger number of spheroids as in TAMR cells.

Conclusion: HOXB5 is one of the key factors involved in tumor aggression and progression in tamoxifen-resistant breast cancer cells.
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1. College of Medicine (의과대학) > Dept. of Anatomy (해부학교실) > 1. Journal Papers
Yonsei Authors
Kim, Myoung Hee(김명희) ORCID logo https://orcid.org/0000-0001-5652-1452
Oh, Ji Hoon(오지훈) ORCID logo https://orcid.org/0000-0001-6619-5515
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