Inhibition of triple negative breast cancer metastasis and invasiveness by novel drugs that target epithelial to mesenchymal transition

Abstract Invasive breast cancer (BrCa) is predicted to affect 1 in 9 women in a lifetime;1 in 32 will die from this disease. The most aggressive forms of BrCa, basal-like/triple-negative phenotype (TNBC), are challenging to treat and result in higher mortality due high number of metastatic cases. Th...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Elizabeth Garcia, Ismat Luna, Kaya L. Persad, Kate Agopsowicz, David A. Jay, Frederick G. West, Mary M. Hitt, Sujata Persad
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5712e87cd26c44929d2ad6ce84bd8c96
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:5712e87cd26c44929d2ad6ce84bd8c96
record_format	dspace
spelling	oai:doaj.org-article:5712e87cd26c44929d2ad6ce84bd8c962021-12-02T18:24:54ZInhibition of triple negative breast cancer metastasis and invasiveness by novel drugs that target epithelial to mesenchymal transition10.1038/s41598-021-91344-72045-2322https://doaj.org/article/5712e87cd26c44929d2ad6ce84bd8c962021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-91344-7https://doaj.org/toc/2045-2322Abstract Invasive breast cancer (BrCa) is predicted to affect 1 in 9 women in a lifetime;1 in 32 will die from this disease. The most aggressive forms of BrCa, basal-like/triple-negative phenotype (TNBC), are challenging to treat and result in higher mortality due high number of metastatic cases. There is a paucity of options for TNBC treatment, which highlights the need for additional innovative treatment approaches. NIH-III mice were injected in the abdominal mammary fat pad with luciferase-expressing derivative of the human TNBC cell line, MDA-MB-231 cells. Animals were gavage-fed with nitrofen at the doses of 1, 3 or 6 mg/kg/alternate days. However, several structural properties/components of nitrofen raise concerns, including its high lipophilicity (cLogP of nearly 5) and a potential toxophore in the form of a nitroarene group. Therefore, we developed analogues of nitrofen which lack the nitro group and/or have replaced the diaryl ether linker with a diarylamine that could allow modulation of polarity. In vitro anti-invasiveness activity of nitrofen analogues were evaluated by quantitative determination of invasion of MDA-MB-231-Luciferase cells through Matrigel using a Boyden chamber. Our in vivo data show that nitrofen efficiently blocks TNBC tumor metastasis. In vitro data suggest that this is not due to cytotoxicity, but rather is due to impairment of invasive capacity of the cells. Further, using an in vitro model of EMT, we show that nitrofen interferes with the process of EMT and promotes mesenchymal to epithelial transformation. In addition, we show that three of the nitrofen analogues significantly reduced invasive potential of TNBC cells, which may, at least partially, be attributed to the analogues’ ability to promote mesenchymal to epithelial-like transformation of TNBC cells. Our study shows that nitrofen, and more importantly its analogues, are significantly effective in limiting the invasive potential of TNBC cell lines with minimal cytotoxic effect. Further, we demonstrate that nitrofen its analogues, are very effective in reversing mesenchymal phenotype to a more epithelial-like phenotype. This may be significant for the treatment of patients with mesenchymal-TNBC tumor subtype who are well known to exhibit high resistance to chemotherapy.Elizabeth GarciaIsmat LunaKaya L. PersadKate AgopsowiczDavid A. JayFrederick G. WestMary M. HittSujata PersadNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Elizabeth Garcia Ismat Luna Kaya L. Persad Kate Agopsowicz David A. Jay Frederick G. West Mary M. Hitt Sujata Persad Inhibition of triple negative breast cancer metastasis and invasiveness by novel drugs that target epithelial to mesenchymal transition
description	Abstract Invasive breast cancer (BrCa) is predicted to affect 1 in 9 women in a lifetime;1 in 32 will die from this disease. The most aggressive forms of BrCa, basal-like/triple-negative phenotype (TNBC), are challenging to treat and result in higher mortality due high number of metastatic cases. There is a paucity of options for TNBC treatment, which highlights the need for additional innovative treatment approaches. NIH-III mice were injected in the abdominal mammary fat pad with luciferase-expressing derivative of the human TNBC cell line, MDA-MB-231 cells. Animals were gavage-fed with nitrofen at the doses of 1, 3 or 6 mg/kg/alternate days. However, several structural properties/components of nitrofen raise concerns, including its high lipophilicity (cLogP of nearly 5) and a potential toxophore in the form of a nitroarene group. Therefore, we developed analogues of nitrofen which lack the nitro group and/or have replaced the diaryl ether linker with a diarylamine that could allow modulation of polarity. In vitro anti-invasiveness activity of nitrofen analogues were evaluated by quantitative determination of invasion of MDA-MB-231-Luciferase cells through Matrigel using a Boyden chamber. Our in vivo data show that nitrofen efficiently blocks TNBC tumor metastasis. In vitro data suggest that this is not due to cytotoxicity, but rather is due to impairment of invasive capacity of the cells. Further, using an in vitro model of EMT, we show that nitrofen interferes with the process of EMT and promotes mesenchymal to epithelial transformation. In addition, we show that three of the nitrofen analogues significantly reduced invasive potential of TNBC cells, which may, at least partially, be attributed to the analogues’ ability to promote mesenchymal to epithelial-like transformation of TNBC cells. Our study shows that nitrofen, and more importantly its analogues, are significantly effective in limiting the invasive potential of TNBC cell lines with minimal cytotoxic effect. Further, we demonstrate that nitrofen its analogues, are very effective in reversing mesenchymal phenotype to a more epithelial-like phenotype. This may be significant for the treatment of patients with mesenchymal-TNBC tumor subtype who are well known to exhibit high resistance to chemotherapy.
format	article
author	Elizabeth Garcia Ismat Luna Kaya L. Persad Kate Agopsowicz David A. Jay Frederick G. West Mary M. Hitt Sujata Persad
author_facet	Elizabeth Garcia Ismat Luna Kaya L. Persad Kate Agopsowicz David A. Jay Frederick G. West Mary M. Hitt Sujata Persad
author_sort	Elizabeth Garcia
title	Inhibition of triple negative breast cancer metastasis and invasiveness by novel drugs that target epithelial to mesenchymal transition
title_short	Inhibition of triple negative breast cancer metastasis and invasiveness by novel drugs that target epithelial to mesenchymal transition
title_full	Inhibition of triple negative breast cancer metastasis and invasiveness by novel drugs that target epithelial to mesenchymal transition
title_fullStr	Inhibition of triple negative breast cancer metastasis and invasiveness by novel drugs that target epithelial to mesenchymal transition
title_full_unstemmed	Inhibition of triple negative breast cancer metastasis and invasiveness by novel drugs that target epithelial to mesenchymal transition
title_sort	inhibition of triple negative breast cancer metastasis and invasiveness by novel drugs that target epithelial to mesenchymal transition
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/5712e87cd26c44929d2ad6ce84bd8c96
work_keys_str_mv	AT elizabethgarcia inhibitionoftriplenegativebreastcancermetastasisandinvasivenessbynoveldrugsthattargetepithelialtomesenchymaltransition AT ismatluna inhibitionoftriplenegativebreastcancermetastasisandinvasivenessbynoveldrugsthattargetepithelialtomesenchymaltransition AT kayalpersad inhibitionoftriplenegativebreastcancermetastasisandinvasivenessbynoveldrugsthattargetepithelialtomesenchymaltransition AT kateagopsowicz inhibitionoftriplenegativebreastcancermetastasisandinvasivenessbynoveldrugsthattargetepithelialtomesenchymaltransition AT davidajay inhibitionoftriplenegativebreastcancermetastasisandinvasivenessbynoveldrugsthattargetepithelialtomesenchymaltransition AT frederickgwest inhibitionoftriplenegativebreastcancermetastasisandinvasivenessbynoveldrugsthattargetepithelialtomesenchymaltransition AT marymhitt inhibitionoftriplenegativebreastcancermetastasisandinvasivenessbynoveldrugsthattargetepithelialtomesenchymaltransition AT sujatapersad inhibitionoftriplenegativebreastcancermetastasisandinvasivenessbynoveldrugsthattargetepithelialtomesenchymaltransition
_version_	1718378095862349824

Inhibition of triple negative breast cancer metastasis and invasiveness by novel drugs that target epithelial to mesenchymal transition

Ejemplares similares