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

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 r...

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Bibliographic Details
Published in:International journal of cancer 2019-10, Vol.145 (7), p.1874-1888
Main Authors: Giulianelli, Sebastián, Riggio, Marina, Guillardoy, Tomas, Pérez Piñero, Cecilia, Gorostiaga, María A., Sequeira, Gonzalo, Pataccini, Gabriela, Abascal, María F., Toledo, María F., Jacobsen, Britta M., Guerreiro, Ana C., Barros, António, Novaro, Virginia, Monteiro, Fátima L., Amado, Francisco, Gass, Hugo, Abba, Martin, Helguero, Luisa A., Lanari, Claudia
Format: Article
Language:English
Subjects:
Activation
Animals
Antiestrogens
Breast cancer
Breast Neoplasms - genetics
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Cancer
Cell growth
Cell Line, Tumor
Cell Proliferation
Endocrine therapy
Enhancer Elements, Genetic
Estrogen Receptor alpha - metabolism
Female
FGF2
Fibroblast growth factor 2
Fibroblast Growth Factor 2 - metabolism
Gene expression
Gene Expression Regulation, Neoplastic
Genomes
Growth factors
hormone receptor interactions
Humans
Isoforms
MCF-7 Cells
Medical research
Mice
MYC
Myc protein
PR isoforms
PRBΔ4
Progesterone
Progesterone receptors
Progestin
Prognosis
Promoter Regions, Genetic
Protein Interaction Maps
Protein Isoforms - genetics
Protein Isoforms - metabolism
Proteins
Proto-Oncogene Proteins c-myc - genetics
Receptors, Progesterone - genetics
Receptors, Progesterone - metabolism
Regulatory sequences
Reporter gene
Survival Analysis
Transcription initiation
Xenograft Model Antitumor Assays
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Summary: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. What's new? Activation of estrogen and progesterone receptors (ERα and PR) may lead breast cancer down the path to hormone‐independent growth and treatment resistance. Here, the authors investigated how fibroblast growth factor 2 (FGF2) promotes interaction between ERα and PR. They showed that FGF2 initiates interaction between ERα and PR at MYC regulatory regions, boosting MYC expression and increasing cell proliferation. They identified 700 proteins recruited to MYC regulatory regions following treatment with FGF2. Among these, 3 were progesterone receptor isoforms, including a novel form called PRBΔ4. These findings open a new path for researching these isoforms as pot
ISSN:0020-7136
1097-0215
DOI:10.1002/ijc.32252