Increased Expression of Follistatin in Breast Cancer Reduces Invasiveness and Clinically Correlates with Better Survival

Abstract

Abstract. Background Follistatin (FST) is a secreted extracellular regulatory protein that binds activin and, with less affinity, related TGFβ superfamily members such as bone morphogenetic proteins (BMPs), preventing access to their receptors (1, 2). Originally thought to act on the pituitary to regulate FSH release, FST has subsequently been noted in many other tissues, in particular co-localising with activin resulting in autocrine and paracrine cellular regulation (1, 3). As an antagonist of activin, FST has diverse regulatory roles in embryogenesis, tissue differentiation and repair, gonadal function and inflammatory and immune processes (3, 4).Three major FST isoforms can be produced, namely FST288 (from splice variant mRNA precursor FST317), FST315 (from splice variant mRNA precursor FST344) and a third FST isoform, FST303, produced from the post-translational truncation of the FST315 C-terminus (5). These three main FST isoforms can also be glycosylated to yield six further FST isoforms (6). FST288 and FST315 are differentially expressed in human tissues, but FST315 is the predominant isoform, whilst the FST288 isoform accounts for less than 5% of the encoded mRNA (6, 7) .The FST/activin interaction has been implicated in tumour proliferation, angiogenesis and metastasis in several solid tumours (8-11). Activin has primarily been seen as an inhibitor of cellular proliferation, although certain cell populations seem to be stimulated by activin. Thus, the overall result of activin/FST action in cancer may be both context and cell type specific (3, 6).In the breast, FST is expressed in the normal mammary gland and in different breast proliferative diseases, with additional experimental evidence suggesting that FST can modulate the breast cancer cell cycle (3,(12)(13)(14). However, its role in breast cancer growth and metastasis is far from clear. In this study we demonstrated a clinical correlation between FST expression and survival in breast cancer, and that overexpression of FST in vitro reduces invasion of breast cancer cells. Patients and MethodsCell lines and patient tissue samples. Human breast cell lines MCF-7,MDA MB 231, ZR-751, BT 549 and BT-20 were obtained from and cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% foetal calf serum and antibiotics (PAA Laboratories Ltd., Somerset, UK). Cells were incubated at 37˚C in 5% CO 2 at 95% humidity.Breast cancer tissue and normal breast tissue samples were collected during surgery at the University Hospital of Wales. In total, 93 tumour samples and 30 normal breast tissue samples were obtained from patients who were enrolled in the study. The tissues obtained during surgery were snap-frozen in liquid nitrogen and stored at −80˚C.

Global DNA Methylation Profiles in Peripheral Blood of WTC-Exposed Community Members with Breast Cancer

“…We observed significant epigenetic differences between these two groups. As expected, several of the genes associated with top differentially methylated probes between these groups have been previously implicated in breast cancer, including SDC2 [42], PBK [43], ALOX12B [44], DAG1 [45], ZNF382 [46], and FST [47]. The promoter of STK11, a high penetrance breast cancer gene [21], was commonly hypermethylated in WTC-exposed breast cancer cases compared to exposed cancer-free controls.…”

Bcl-2 dependent modulation of Hippo pathway in cancer cells

“…CCND3 is a biomarker component of differentially expressed mRNA signature in melanoma respect to normal tissues [ 42 ], and is related to survival outcomes in triple negative breast cancer patients [ 43 ]. FST mediates the ability of YAP to stimulate cell invasion in melanoma [ 23 , 44 ], and its expression correlates with metastasis in a breast cancer mouse model [ 45 ] and with survival outcomes in cancer patients [ 46 ]. MYC is involved in tumor progression [ 47 ] and in the response to therapy of both melanoma [ 48 ] and breast carcinoma [ 49 ].…”

Genomic Loss and Epigenetic Silencing of the FOSL1 Tumor Suppressor Gene in Radiation-induced Neoplastic Transformation of Human CGL1 Cells Alters the Tumorigenic Phenotype In Vitro and In Vivo

“…Additionally, the upregulation of Fst in iPG pathway perturbation analysis was proposed to as well upregulate Tgfβ signaling. Fst has also been shown to be an inhibitor of metastasis and invasiveness of cancer ( 50–52 ). Although further functional assay validation is warranted, it is proposed that FRA1 re-expression may recover previously observed downregulation of the canonical Tgfβ signaling in tumorigenic GIM vs. non-tumorigenic CON analysis.…”