Prosaposin, a regulator of estrogen receptor alpha, promotes breast cancer growth

Abstract

Prosaposin, a secreted protein, is a well-known pleiotropic growth factor. Although a previous report has indicated that prosaposin is overexpressed in breast cancer cell lines, the role of prosaposin in the development of breast cancer remains to be identified. Here, we first revealed that prosaposin upregulated estrogen receptor alpha expression, nuclear translocation and transcriptional activity by western blot, immunofluorescence assay and dual luciferase reporter gene assay, respectively. Furthermore, we demonstrated prosaposin upregulated estrogen receptor alpha expression through MAPK-signaling pathway using MAPK inhibitor. Proliferation assay and tumor xenograft experiments in nude mice (n = 6 per group) further confirmed prosaposin could promote breast cancer growth significantly in vitro and in vivo. These findings suggested that prosaposin might enhance estrogen receptor alpha-mediated signaling axis and play a role in breast cancer development and progression. (Cancer Sci 2012; 103: 1820-1825 B reast cancer is the most common malignancy and the main cause of death from cancers in women.(1) The carcinogenesis of breast cancer is frequently hormone-dependent. The female sex-steroid hormone estrogen 17b-estradiol (E2) plays a prominent role in mediating the maturation, proliferation, differentiation, and influences the growth and development of breast cancer.(2) Numerous studies have indicated that E2 can induce and promote breast cancer and this process is mediated primarily by estrogen receptor alpha (ERa). (3)(4)(5) Estrogen receptor (ER) is a member of the steroid/nuclear receptor family of transcription regulators, while ERa is the predominant receptor isoform expressed in breast cancer. Approximately 70% of breast cancer patients score positive for ERa at diagnosis.(6-9) Estrogen receptor alpha promotes cell growth, metastasis and also mediates resistance to apoptosis or immunosurveillance in breast cancer. (10)(11)(12) Prosaposin (PSAP) exists as a secretory protein (70 kDa) as well as a lysosomal protein (65 kDa). The molecular weight difference depends on the post-translational glycosylation. (13) Lysosomal PSAP is the precursor of four sphingolipid activator proteins (saposin A-D) and is involved in hydrolysis of sphingolipids within lysosome.(14) Secretory PSAP is a well-known pleiotropic growth factor found in secretory body fluid, such as seminal plasma, bile, cerebrospinal fluid, human milk, (15,16) as well as neuronal surface membrane.(17) The distribution of PSAP suggests it may have some specific extracellular functions. PSAP-deficiency in human and mice is lethal. (18,19) Prosaposin knock-out mice also present with a series of developmental abnormalities in the nervous system and male reproductive organs. (18,20) Recent investigations show that PSAP could prevent cell death or apoptosis and promote cell survival. (21,22) Koochekpour et al. (23) focus on the function of PSAP in prostate cancer and find PSAP is overexpressed in prostate cancer, and also upregulates androgen receptor (...

Mechano-Signal Transduction in Mesenchymal Stem Cells Induces Prosaposin Secretion to Drive the Proliferation of Breast Cancer Cells

“…6B). To further understand the mechanism of action for PSAP, we analyzed phosphorylation of ERK and Akt in 4T1 cells, because PSAP induces phosphorylation of ERK and growth of breast cancer cells(13) and saposin C, including the functional domain of PSAP, promotes survival of prostate cancer cells via Akt phosphorylation(14). PSAP treatment induced phosphorylation of Akt at T308 (Fig.…”

“…6I). Previous studies showed that PSAP induces mammary cancer growth(13) and inhibits metastasis(15). Our results are consistent with these reports.…”

“…In addition to the function in lysosome, PSAP is also secreted as full-length prosaposin that regulates neurotrophic action in the nerve system(12). Recently, PSAP was reported to promote ERK (Mapk1) activation and breast cancer growth(13) and saposin C, active domain of PSAP, enhances survival via Akt activation in prostate cancer cells(14). In contrast, PSAP inhibits metastasis via stimulating the expression of thorombospondin-1 in fibroblasts present in tumor(15).…”

Candidate genes and pathways downstream of PAX8 involved in ovarian high-grade serous carcinoma

“…Hence, we focused our attention on the intersections between SKOV-3 and FT194 cells and we observed that they include several interesting genes such as: PSAP, FGF18, CDH6, ROR1, RBPJ and DNMT3B whose role in cell proliferation, cell survival and tumorigenic process has already been reported. In particular, PSAP (prosaposin) is a pleiotropic growth factor able to prevent cell death or apoptosis and to promote cell survival [68]; FGF18 controls migration, invasion and tumorigenicity of ovarian cancer cells [69]; CDH6 is a new TGF-beta target modulated as a mesenchymal marker in EMT [52]; ROR1, a receptor tyrosine kinase orphan receptor 1, is involved in migration, invasion and EMT in ovarian cancer cells [70]; RBPJ (recombination signal-binding protein Jk) is a key transcription factor in the Notch signaling pathway and its inhibition reduces cell growth [71]; DNMT3B encodes a DNA methyltransferase involved in de novo DNA methylation whose role in cancer development is not clear but several reports suggest a role as tumor suppressor [72]. …”

Detection of Prosaposin and Mature Saposins in Goat Milk

“…Other studies, have evaluated the potential of Prosaposin as an important molecule in the protection of cancer cells, such as prostate (Koochekpour et. al, 2012) and breast cancer cells (Wu et al, 2012), enabling them to survive and proliferate, also suggesting the presents of Prosaposin as a potential drug target in the development of treatments for personal cancer therapies. Patton et al (1997) demonstrated the presence of Prosaposins in human, cow and goat's milks.…”