Breast cancer-associated fibroblasts: their roles in tumor initiation, progression and clinical applications

Qiao, Aixiu; Gu, Feng; Guo, Xiaojing; Zhang, Xinmin; Fu, Li

doi:10.1007/s11684-016-0431-5

Cited by 61 publications

(65 citation statements)

References 98 publications

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“…These results illustrate one mechanism by which tumor and local stroma gene expression are positively correlated. Similar positive feedback loops have been described for cancer-associated fibroblasts as well29.…”

Section: Discussionsupporting

confidence: 74%

Gene expression in local stroma reflects breast tumor states and predicts patient outcome

Bainer

Frankenberger

Rabe

et al. 2016

Sci Rep

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The surrounding microenvironment has been implicated in the progression of breast tumors to metastasis. However, the degree to which metastatic breast tumors locally reprogram stromal cells as they disrupt tissue boundaries is not well understood. We used species-specific RNA sequencing in a mouse xenograft model to determine how the metastasis suppressor RKIP influences transcription in a panel of paired tumor and stroma tissues. We find that gene expression in metastatic breast tumors is pervasively correlated with gene expression in local stroma of both mouse xenografts and human patients. Changes in stromal gene expression elicited by tumors better predicts subtype and patient survival than tumor gene expression, and genes with coordinated expression in both tissues predict metastasis-free survival. These observations support the use of stroma-based strategies for the diagnosis and prognosis of breast cancer.

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Section: Discussionsupporting

confidence: 74%

Gene expression in local stroma reflects breast tumor states and predicts patient outcome

Bainer

Frankenberger

Rabe

et al. 2016

Sci Rep

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“…Fibroblasts are key players in tumorigenesis and constitute the majority of stromal cells within a tumor, especially in breast, prostate, and pancreatic cancers18. To elucidate the mechanisms of the different tumorigenic abilities between the estrogen group and the control group, we compared the mRNA levels of several tumor-promoting factors produced by CAFs in 4T1 and EMT6 xenografts192021. After a comprehensive assessment, we found that the levels of SDF-1α (CXCL12) in the estrogen group were significantly increased (Fig.…”

Section: Resultsmentioning

confidence: 99%

Estrogen-induced SDF-1α production promotes the progression of ER-negative breast cancer via the accumulation of MDSCs in the tumor microenvironment

Ouyang

Chang

Fang

et al. 2016

Sci Rep

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Estrogen plays a role in the processes of tumorigenesis, metastasis, and drug resistance in estrogen receptor (ER)-positive breast cancer (BC). Whether estrogen contributes to ER-negative BC is unclear. Here, we aimed to investigate whether estrogen could stimulate the secretion of stromal-derived factor-1 (SDF-1α) by cancer-associated fibroblasts (CAFs) to promote the progression of ER-negative BC. We transplanted ER-negative BC cells into ovariectomized mice, which was followed by continuous injection of estrogen, and found that estrogen promoted the tumorigenesis of BC. Furthermore, High levels of SDF-1α and tumor-infiltrating myeloid-derived suppressor cells (MDSCs) were detected in the estrogen treatment group. Estrogen stimulates secretion of SDF-1α by CAFs extracted from BC patients. Recombinant SDF-1α could recruit MDSCs isolated from bone marrow cells of mice. In addition, the co-culture of CAFs and MDSCs demonstrated that the recruitment of MDSCs was increased when CAFs were exposed to estrogen. Using AMD3100 to block the SDF-1α/CXCR4 axis or gemcitabine to delete MDSCs, we observed that both of these agents could neutralize the effect of estrogen on tumorigenesis. Together, these results suggest that estrogen may promote the progression of ER-negative BC by stimulating CAFs to secrete SDF-1α, which can recruit MDSCs to the tumor microenvironment to exert tumor-promoting effects.

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“…In this study, we propose that autocrine or paracrine FGF2, probably produced by stromal CAFs, activates FGFRs and downstream signaling pathways, which in turn activate ERα and classic and novel PR isoforms. These activated receptors form complexes that play key roles inducing the transcription of MYC , a master cancer gene.…”

Section: Discussionmentioning

confidence: 98%

FGF2 induces breast cancer growth through ligand‐independent activation and recruitment of ERα and PRBΔ4 isoform to MYC regulatory sequences

Giulianelli

Riggio

Guillardoy

et al. 2019

Intl Journal of Cancer

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Progression to hormone‐independent growth leading to endocrine therapy resistance occurs in a high proportion of patients with estrogen receptor alpha (ERα) and progesterone receptors (PR) positive breast cancer. We and others have previously shown that estrogen‐ and progestin‐induced tumor growth requires ERα and PR interaction at their target genes. Here, we show that fibroblast growth factor 2 (FGF2)‐induces cell proliferation and tumor growth through hormone‐independent ERα and PR activation and their interaction at the MYC enhancer and proximal promoter. MYC inhibitors, antiestrogens or antiprogestins reverted FGF2‐induced effects. LC–MS/MS identified 700 canonical proteins recruited to MYC regulatory sequences after FGF2 stimulation, 397 of which required active ERα (ERα‐dependent). We identified ERα‐dependent proteins regulating transcription that, after FGF2 treatment, were recruited to the enhancer as well as proteins involved in transcription initiation that were recruited to the proximal promoter. Also, among the ERα‐dependent and independent proteins detected at both sites, PR isoforms A and B as well as the novel protein product PRBΔ4 were found. PRBΔ4 lacks the hormone‐binding domain and was able to induce reporter gene expression from estrogen‐regulated elements and to increase cell proliferation when cells were stimulated with FGF2 but not by progestins. Analysis of the Cancer Genome Atlas data set revealed that PRBΔ4 expression is associated with worse overall survival in luminal breast cancer patients. This discovery provides a new mechanism by which growth factor signaling can engage nonclassical hormone receptor isoforms such as PRBΔ4, which interacts with growth‐factor activated ERα and PR to stimulate MYC gene expression and hence progression to endocrine resistance.

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Breast cancer-associated fibroblasts: their roles in tumor initiation, progression and clinical applications

Cited by 61 publications

References 98 publications

Gene expression in local stroma reflects breast tumor states and predicts patient outcome

Gene expression in local stroma reflects breast tumor states and predicts patient outcome

Estrogen-induced SDF-1α production promotes the progression of ER-negative breast cancer via the accumulation of MDSCs in the tumor microenvironment

FGF2 induces breast cancer growth through ligand‐independent activation and recruitment of ERα and PRBΔ4 isoform to MYC regulatory sequences

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