Vitamin D analogues exhibit antineoplastic activity in breast cancer patient-derived xenograft cells

[Display omitted] •EM1 and UVB1 reduce the viability of cells derived from HER2-positive and TNBC PDXs.•UVB1 has antiproliferative actions in Trastuzumab-emtansine (T-DM1) resistant cells.•UVB1 impairs the organoids formation capacity in T-DM1 resistant cells.•UVB1 inhibits the growth of established...

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Published in:The Journal of steroid biochemistry and molecular biology 2021-04, Vol.208, p.105735-105735, Article 105735
Main Authors: Ferronato, María Julia, Nadal Serrano, Mercedes, Arenas Lahuerta, Enrique Javier, Bernadó Morales, Cristina, Paolillo, Giuliana, Martinez-Sabadell Aliguer, Alex, Santalla, Hugo, Mascaró, Marilina, Vitale, Cristian, Fall, Yagamare, Arribas, Joaquín, Facchinetti, María Marta, Curino, Alejandro Carlos
Format: Article
Language:English
Subjects:
Analogue
Animal models
Animals
Antitumor activity
Antitumor agents
Breast cancer
Breast Neoplasms - drug therapy
Breast Neoplasms - genetics
Breast Neoplasms - pathology
Calcitriol
Cell culture
Cell Line, Tumor
Cell Proliferation - drug effects
Disease Models, Animal
EM1
ErbB-2 protein
Female
Gene Expression Regulation, Neoplastic - drug effects
Humans
Hypercalcemia
Mice
Organoids
Patient-derived xenograft
Quality of Life
Trastuzumab
Triple Negative Breast Neoplasms - drug therapy
Triple Negative Breast Neoplasms - genetics
Triple Negative Breast Neoplasms - pathology
UVB1
Vitamin D
Vitamin D - analogs & derivatives
Vitamin D - pharmacology
Vitamin D receptors
Xenograft Model Antitumor Assays
Xenografts
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Summary:[Display omitted] •EM1 and UVB1 reduce the viability of cells derived from HER2-positive and TNBC PDXs.•UVB1 has antiproliferative actions in Trastuzumab-emtansine (T-DM1) resistant cells.•UVB1 impairs the organoids formation capacity in T-DM1 resistant cells.•UVB1 inhibits the growth of established organoids derived from T-DM1 resistant cells.•VDR expression in PDXs positively correlates with UVB1 antitumor response. 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.
ISSN:0960-0760
1879-1220
DOI:10.1016/j.jsbmb.2020.105735