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

Abstract

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.

Circular RNA circ_001422 Promotes Progression and Metastasis of Osteosarcoma via the miR-195-5p/FGF2/PI3K/Akt Axis

“…7f and g). Interestingly, FGF2 has been widely identi ed as an oncogene to participate in tumorigenesis and metastasis of multiple cancer types [18][19][20]. Thus, we presumed that circ_001422 might contribute to the malignant progression of OS via protecting FGF2 from degradation induced by miR-195-5p.…”

FGF/FGFR signaling in health and disease

“… 652 FGF2 can induce breast cancer growth through ligand-independent activation and stimulate the MYC gene expression through recruitment of ERα and PRB 4 isoform to MYC regulatory sequences. 653 The results from Betsuyaku, T.’s group showed that the FGF2 aptamer that can block FGF2 activity could inhibit the growth of FGF2-FGFR pathway-dependent lung cancer cells. 654 Increased expression of FGF4 in ovarian cancer stem-like cells/cancer-initiating cells is involved in the upregulating tumor initiation capacity of fibroblasts.…”

Expression and Function of C1orf132 Long-Noncoding RNA, in Breast Cancer Cell Lines and Tissues

“…In this way, N-cadherin increases tumor cell interactions with endothelial and mesenchymal cells 25 . On the other hand, broblast growth factor 2 (FGF2) which can induce proliferation of neoplastic cell and tumor hormone-independent growth 30 , is a tumor cell survival factor, which inhibits cell apoptosis through an autocrine secretory loop. In addition, FGF2 can be an activator of angiogenesis during tumor mass growth and metastasis 31 .…”