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Vitamin D analogues exhibit antineoplastic activity in breast cancer patient-derived xenograft cells
María Julia Ferronato1, Mercedes Nadal Serrano2, Enrique Javier Arenas Lahuerta2
1Laboratorio de Biología del Cáncer, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Universidad Nacional del Sur (UNS) - CONICET, Departamento de Biología, Bioquímica y Farmacia (UNS), Bahía Blanca, Argentina.
Abstract:
Despite advances in breast cancer (BC) treatment, its mortality remains high due to intrinsic or acquired resistance to therapy. Several ongoing efforts are being made to develop novel drugs to treat this pathology with the aim to overcome resistance, prolong patient survival and improve their quality of life. We have previously shown that the non-hypercalcemic vitamin D analogues EM1 and UVB1 display antitumor effects in preclinical studies employing conventional cell lines and animal models developed from these cells. In this work, we explored the antitumor effects of EM1 and UVB1 employing BC cells derived from patient-derived xenografts (PDXs), which are a powerful preclinical tool for testing new drugs. We demonstrated that the analogues reduced the viability of HER2-positive and Triple Negative BC-PDXs. Moreover, using an in vitro model of acquired resistance to Trastuzumab-emtansine, UVB1 displayed anti-proliferative actions under 2D and 3D culture conditions. It inhibited both formation and growth of established organoids. In addition, a direct correlation between UVB1 antitumor effects and VDR expression in PDXs was found. In conclusion, all the results reinforce the potential use of these vitamin D analogues as antitumor agents to treat HER2-positive and Triple Negative BC.
Insights
Novel vitamin D analogues, EM1 and UVB1, show promise in reducing breast cancer cell viability, particularly in HER2-positive and Triple Negative subtypes. UVB1 also demonstrated anti-proliferative effects in drug-resistant models.
Area of Science:
- Oncology
- Endocrinology
- Pharmacology
Background:
- Breast cancer (BC) poses a significant mortality challenge due to treatment resistance.
- Developing novel therapeutic agents is crucial to overcome resistance and improve patient outcomes.
- Non-hypercalcemic vitamin D analogues have shown preclinical antitumor potential.
Purpose of the Study:
- To evaluate the antitumor effects of vitamin D analogues EM1 and UVB1 in patient-derived xenograft (PDX) models of breast cancer.
- To investigate the efficacy of UVB1 in a model of acquired resistance to Trastuzumab-emtansine.
- To explore the correlation between UVB1's efficacy and Vitamin D Receptor (VDR) expression.
Main Methods:
- Utilized breast cancer cells derived from patient-derived xenografts (PDXs).
- Assessed the viability of HER2-positive and Triple Negative BC-PDXs upon treatment with EM1 and UVB1.
- Investigated UVB1's anti-proliferative effects in 2D and 3D cultures, including organoid models with acquired Trastuzumab-emtansine resistance.
- Correlated UVB1's antitumor activity with VDR expression levels in PDXs.
Main Results:
- EM1 and UVB1 reduced the viability of HER2-positive and Triple Negative BC-PDXs.
- UVB1 exhibited anti-proliferative activity in both 2D and 3D culture models, including those with acquired resistance.
- UVB1 inhibited the formation and growth of resistant breast cancer organoids.
- A direct correlation was observed between UVB1's antitumor effects and VDR expression in PDXs.
Conclusions:
- These findings support the potential of vitamin D analogues EM1 and UVB1 as novel therapeutic agents for HER2-positive and Triple Negative breast cancer.
- UVB1 demonstrates efficacy against drug-resistant breast cancer models, highlighting its therapeutic potential.
- VDR expression may serve as a predictive marker for UVB1 response in breast cancer treatment.
