FGFR1 Overexpression Induces Cancer Cell Stemness and Enhanced Akt/Erk-ER Signaling to Promote Palbociclib Resistance in Luminal A Breast Cancer Cells

Resistance to CDK4/6 inhibitors (CDKis) is emerging as a clinical challenge. Identification of the factors contributing to CDKi resistance, with mechanistic insight, is of pivotal significance. Recent studies linked aberrant FGFR signaling to CDKi resistance. However, detailed mechanisms are less cl...

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Autores principales:	Qiong Cheng, Zhikun Ma, Yujie Shi, Amanda B. Parris, Lingfei Kong, Xiaohe Yang
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	FGFR1 palbociclib CDK4/6 inhibitor resistance breast cancer cancer stem cells cyclins/CDKs Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/38f749d3ca5843bd8db0c6c7fa6acc84
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spelling	oai:doaj.org-article:38f749d3ca5843bd8db0c6c7fa6acc842021-11-25T17:10:22ZFGFR1 Overexpression Induces Cancer Cell Stemness and Enhanced Akt/Erk-ER Signaling to Promote Palbociclib Resistance in Luminal A Breast Cancer Cells10.3390/cells101130082073-4409https://doaj.org/article/38f749d3ca5843bd8db0c6c7fa6acc842021-11-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/3008https://doaj.org/toc/2073-4409Resistance to CDK4/6 inhibitors (CDKis) is emerging as a clinical challenge. Identification of the factors contributing to CDKi resistance, with mechanistic insight, is of pivotal significance. Recent studies linked aberrant FGFR signaling to CDKi resistance. However, detailed mechanisms are less clear. Based on control and FGFR1 overexpressing luminal A cell line models, we demonstrated that FGFR1 overexpression rendered the cells resistant to palbociclib. FGFR1 overexpression abolished palbociclib-mediated cell cycle arrest, as well as the attenuated palbociclib-induced inhibition of G1/S transition regulators (pRb, E2F1, and cyclin D3) and factors that promote G2/M transition (cyclin B1, cdc2/CDK1, and cdc25). Importantly, FGFR1-induced palbociclib resistance was associated with promotion of cancer cell stemness and the upregulation of Wnt/β-catenin signaling. We found that palbociclib may function as an ER agonist in MCF-7/FGFR1 cells. Upregulation of the ER-mediated transcription in MCF-7/FGFR1 cells was associated with ERα phosphorylation and enhanced receptor tyrosine kinase signaling. The combination of palbociclib with FGFR-targeting AZD4547 resulted in remarkable synergistic effects on MCF-7/FGFR1 cells, especially for the inhibition of cancer cell stemness. Our findings of FGFR1-induced palbociclib resistance, promotion of cancer stem cells and associated molecular changes advance our mechanistic understanding of CDKi resistance, which will facilitate the development of strategies targeting CDKi resistance in breast cancer treatment.Qiong ChengZhikun MaYujie ShiAmanda B. ParrisLingfei KongXiaohe YangMDPI AGarticleFGFR1palbociclibCDK4/6 inhibitor resistancebreast cancercancer stem cellscyclins/CDKsBiology (General)QH301-705.5ENCells, Vol 10, Iss 3008, p 3008 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	FGFR1 palbociclib CDK4/6 inhibitor resistance breast cancer cancer stem cells cyclins/CDKs Biology (General) QH301-705.5
spellingShingle	FGFR1 palbociclib CDK4/6 inhibitor resistance breast cancer cancer stem cells cyclins/CDKs Biology (General) QH301-705.5 Qiong Cheng Zhikun Ma Yujie Shi Amanda B. Parris Lingfei Kong Xiaohe Yang FGFR1 Overexpression Induces Cancer Cell Stemness and Enhanced Akt/Erk-ER Signaling to Promote Palbociclib Resistance in Luminal A Breast Cancer Cells
description	Resistance to CDK4/6 inhibitors (CDKis) is emerging as a clinical challenge. Identification of the factors contributing to CDKi resistance, with mechanistic insight, is of pivotal significance. Recent studies linked aberrant FGFR signaling to CDKi resistance. However, detailed mechanisms are less clear. Based on control and FGFR1 overexpressing luminal A cell line models, we demonstrated that FGFR1 overexpression rendered the cells resistant to palbociclib. FGFR1 overexpression abolished palbociclib-mediated cell cycle arrest, as well as the attenuated palbociclib-induced inhibition of G1/S transition regulators (pRb, E2F1, and cyclin D3) and factors that promote G2/M transition (cyclin B1, cdc2/CDK1, and cdc25). Importantly, FGFR1-induced palbociclib resistance was associated with promotion of cancer cell stemness and the upregulation of Wnt/β-catenin signaling. We found that palbociclib may function as an ER agonist in MCF-7/FGFR1 cells. Upregulation of the ER-mediated transcription in MCF-7/FGFR1 cells was associated with ERα phosphorylation and enhanced receptor tyrosine kinase signaling. The combination of palbociclib with FGFR-targeting AZD4547 resulted in remarkable synergistic effects on MCF-7/FGFR1 cells, especially for the inhibition of cancer cell stemness. Our findings of FGFR1-induced palbociclib resistance, promotion of cancer stem cells and associated molecular changes advance our mechanistic understanding of CDKi resistance, which will facilitate the development of strategies targeting CDKi resistance in breast cancer treatment.
format	article
author	Qiong Cheng Zhikun Ma Yujie Shi Amanda B. Parris Lingfei Kong Xiaohe Yang
author_facet	Qiong Cheng Zhikun Ma Yujie Shi Amanda B. Parris Lingfei Kong Xiaohe Yang
author_sort	Qiong Cheng
title	FGFR1 Overexpression Induces Cancer Cell Stemness and Enhanced Akt/Erk-ER Signaling to Promote Palbociclib Resistance in Luminal A Breast Cancer Cells
title_short	FGFR1 Overexpression Induces Cancer Cell Stemness and Enhanced Akt/Erk-ER Signaling to Promote Palbociclib Resistance in Luminal A Breast Cancer Cells
title_full	FGFR1 Overexpression Induces Cancer Cell Stemness and Enhanced Akt/Erk-ER Signaling to Promote Palbociclib Resistance in Luminal A Breast Cancer Cells
title_fullStr	FGFR1 Overexpression Induces Cancer Cell Stemness and Enhanced Akt/Erk-ER Signaling to Promote Palbociclib Resistance in Luminal A Breast Cancer Cells
title_full_unstemmed	FGFR1 Overexpression Induces Cancer Cell Stemness and Enhanced Akt/Erk-ER Signaling to Promote Palbociclib Resistance in Luminal A Breast Cancer Cells
title_sort	fgfr1 overexpression induces cancer cell stemness and enhanced akt/erk-er signaling to promote palbociclib resistance in luminal a breast cancer cells
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/38f749d3ca5843bd8db0c6c7fa6acc84
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FGFR1 Overexpression Induces Cancer Cell Stemness and Enhanced Akt/Erk-ER Signaling to Promote Palbociclib Resistance in Luminal A Breast Cancer Cells

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