Amphiregulin retains ERα expression in acquired aromatase inhibitor resistant breast cancer cells

Wang, Yuanzhong; Tzeng, Yen‐Dun Tony; Chang, Gregory; Wang, Xiaoqiang; Chen, Shiuan

doi:10.1530/erc-20-0258

Cited by 6 publications

(3 citation statements)

References 40 publications

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“…The association between the oestrogen‐regulated gene expression (e.g., PGR , AREG ) and the oestrogen‐dependent growth has been extensively investigated 54–58 . Previous studies mainly used breast cancer cell lines, especially MCF‐7, which are known to show concomitant up‐regulation of oestrogen‐responsive genes and cell proliferation genes within the same cell responding to oestrogen.…”

Section: Discussionmentioning

confidence: 99%

“…The association between the oestrogen‐regulated gene expression (e.g., PGR , AREG ) and the oestrogen‐dependent growth has been extensively investigated. 54 , 55 , 56 , 57 , 58 Previous studies mainly used breast cancer cell lines, especially MCF‐7, which are known to show concomitant up‐regulation of oestrogen‐responsive genes and cell proliferation genes within the same cell responding to oestrogen. The results in the current study on the tumour models with the cells showing heterogenous gene expression indicated that the expansion of cells expressing typical oestrogen‐regulated genes like PGR would not be directly associated with oestrogen‐mediated proliferation.…”

Section: Discussionmentioning

confidence: 99%

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Molecular features of luminal breast cancer defined through spatial and single‐cell transcriptomics

Yoshitake,

Mori,

et al. 2024

Clinical & Translational Med

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BackgroundIntratumour heterogeneity is a hallmark of most solid tumours, including breast cancers. We applied spatial transcriptomics and single‐cell RNA‐sequencing on patient‐derived xenografts (PDXs) to profile spatially resolved cell populations within oestrogen receptor‐positive (ER+) breast cancer and to elucidate their importance in oestrogen‐dependent tumour growth.MethodsTwo PDXs of ‘ER‐high’ breast cancers with opposite oestrogen‐mediated growth responses were investigated: oestrogen‐suppressed GS3 (80–100% ER) and oestrogen‐dependent SC31 (40–90% ER) models. The observation was validated via single‐cell analyses on an ‘ER‐low’ PDX, GS1 (5% ER). The results from our spatial and single‐cell analyses were further supported by a public ER+ breast cancer single‐cell dataset and protein‐based dual immunohistochemistry (IHC) of SC31 examining important luminal cancer markers (i.e., ER, progesterone receptor and Ki67). The translational implication of our findings was assessed by clinical outcome analyses on publicly available cohorts.ResultsOur space‐gene‐function study revealed four spatially distinct compartments within ER+ breast cancers. These compartments showed functional diversity (oestrogen‐responsive, proliferative, hypoxia‐induced and inflammation‐related). The ‘proliferative’ population, rather than the ‘oestrogen‐responsive’ compartment, was crucial for oestrogen‐dependent tumour growth, leading to the acquisition of luminal B‐like features. The cells expressing typical oestrogen‐responsive genes like PGR were not directly linked to oestrogen‐dependent proliferation. Dual IHC analyses demonstrated the distinct contribution of the Ki67+ proliferative cells toward oestrogen‐mediated growth and their response to a CDK4/6 inhibitor. The gene signatures derived from the proliferative, hypoxia‐induced and inflammation‐related compartments were significantly correlated with worse clinical outcomes, while patients with the oestrogen‐responsive signature showed better prognoses, suggesting that this compartment would not be directly associated with oestrogen‐dependent tumour progression.ConclusionsOur study identified the gene signature in our ‘proliferative’ compartment as an important determinant of luminal cancer subtypes. This ‘proliferative’ cell population is a causative feature of luminal B breast cancer, contributing toward its aggressive behaviours.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Molecular features of luminal breast cancer defined through spatial and single‐cell transcriptomics

Yoshitake,

Mori,

et al. 2024

Clinical & Translational Med

Self Cite

View full text Add to dashboard Cite

show abstract

“…The association between the estrogen-regulated gene expression (e.g., PGR, AREG) and the estrogen-dependent growth has been extensively investigated [38][39][40][41][42]. Previous studies mainly used breast cancer cell lines, especially MCF-7, which are known to show concomitant upregulation of estrogen-responsive genes and cell proliferation genes within the same cell responding to estrogen.…”

Section: Discussionmentioning

confidence: 99%

Identification and characterization of a proliferative cell population in estrogen receptor-positive metastatic breast cancer through spatial and single-cell transcriptomics

Yoshitake

Mori

et al. 2023

Preprint

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Background Intratumor heterogeneity is a hallmark of most solid tumors, including breast cancers. We applied spatial transcriptomics and single-cell RNA-sequencing technologies to profile spatially resolved cell populations within estrogen receptor-positive ER+) metastatic breast cancers and elucidate their importance in estrogen-dependent tumor growth. Methods Spatial transcriptomics and single-cell RNA-sequencing were performed on two patient-derived xenografts (PDXs) of 'ER-high' metastatic breast cancers with opposite estrogen-mediated growth responses: estrogen-suppressed GS3 (80-100% ER) and estrogen-stimulated SC31 (30-75% ER) models. The analyses included samples treated with and without 17beta-estradiol. The findings were validated via scRNA-seq analyses on 'ER-low' estrogen-accelerating PDX, GS1 (5% ER). The results from our spatial and single-cell analyses were further supported by the analysis of a publicly available single cell dataset and a protein-based dual immunohistochemical (IHC) evaluation using three important clinical markers [i.e., ER, progesterone receptor (PR), and Ki67]. The translational implication of these results was assessed by clinical outcome analyses on public breast cancer cohorts. Results Our novel space-gene-function study revealed a 'proliferative' cell population in addition to three major spatially distinct compartments within ER+ metastatic breast cancers. These compartments showed functional diversity (i.e., estrogen-responsive, proliferative, hypoxia-induced, and inflammation-related). The 'proliferative (MKI67+)' population, not 'estrogen-responsive' compartment, was crucial for estrogen-dependent tumor growth, leading to the acquisition of luminal B features. The cells with induction of typical estrogen-responsive genes such as PGR were not directly linked to estrogen-dependent proliferation. Additionally, the dual IHC analyses demonstrated the distinct contribution of the Ki67+ proliferative cells toward estrogen-mediated growth and their response to palbociclib, a CDK4/6 inhibitor. The gene signatures developed from the proliferative, hypoxia-induced, and inflammation-related compartments were significantly correlated with worse clinical outcomes, while patients with the high estrogen-responsive scores showed better prognosis, confirming that the estrogen-responsive compartment would not be directly associated with estrogen-dependent tumor progression. Conclusions For the first time, our study elucidated a 'proliferative' cell population distinctly distributed in ER+ metastatic breast cancers. They contribute differently toward progression of these cancers, and the gene signature in the 'proliferative' compartment is an important determinant of luminal cancer subtypes.

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Mitochondrial stress adaptation promotes resistance to aromatase inhibitor in human breast cancer cells via ROS/calcium up-regulated amphiregulin–estrogen receptor loop signaling

et al. 2021

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Amphiregulin retains ERα expression in acquired aromatase inhibitor resistant breast cancer cells

Cited by 6 publications

References 40 publications

Molecular features of luminal breast cancer defined through spatial and single‐cell transcriptomics

Molecular features of luminal breast cancer defined through spatial and single‐cell transcriptomics

Identification and characterization of a proliferative cell population in estrogen receptor-positive metastatic breast cancer through spatial and single-cell transcriptomics

Mitochondrial stress adaptation promotes resistance to aromatase inhibitor in human breast cancer cells via ROS/calcium up-regulated amphiregulin–estrogen receptor loop signaling

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