PES1 promotes breast cancer by differentially regulating ERα and ERβ

Abstract

The initiation of breast cancer is associated with increased expression of tumor-promoting estrogen receptor α (ERα) protein and decreased expression of tumor-suppressive ERβ protein. However, the mechanism underlying this process is unknown. Here we show that PES1 (also known as Pescadillo), an estrogen-inducible protein that is overexpressed in breast cancer, can regulate the balance between ERα and ERβ. We found that PES1 modulated many estrogen-responsive genes by enhancing the transcriptional activity of ERα while inhibiting transcriptional activity of ERβ. Consistent with this regulation of ERα and ERβ transcriptional activity, PES1 increased the stability of the ERα protein and decreased that of ERβ through the ubiquitin-proteasome pathway, mediated by the carboxyl terminus of Hsc70-interacting protein (CHIP). Moreover, PES1 transformed normal human mammary epithelial cells and was required for estrogen-induced breast tumor growth in nude mice. Further analysis of clinical samples showed that expression of PES1 correlated positively with ERα expression and negatively with ERβ expression and predicted good clinical outcome in breast cancer. Our data demonstrate that PES1 contributes to breast tumor growth through regulating the balance between ERα and ERβ and may be a better target for the development of drugs that selectively regulate ERα and ERβ activities. IntroductionThe association between estrogen and breast cancer was recognized over 100 years ago. Estrogen exerts its function through its 2 nuclear receptors, estrogen receptor α (ERα) and ERβ (1, 2). ER belongs to a superfamily of ligand-activated transcription factors that share structural similarity characterized by several functional domains. N-terminal estrogen-independent and C-terminal estrogen-dependent activation function domains (AF1 and AF2, respectively) contribute to the transcriptional activity of the 2 receptors. The DNAbinding domain of the ERs is centrally located. The ligand-binding domain, overlapping AF2, shows 58% homology between ERα and ERβ. The DNA-binding domain is identical between the 2 receptors, except for 3 amino acids. However, the AF1 domain of ERβ has only 28% homology with that of ERα. The binding of estrogen to ER leads to ER dimerization and its recruitment to the estrogenresponsive elements (EREs) on the promoters of ER target genes, thereby either enhancing or repressing gene activation.The development of breast cancer is associated with dysregulation of ER expression (3-8). Compared with that in normal breast tissues, the proportion of cells expressing ERα is increased, whereas ERβ expression is reduced, in hormone-dependent breast tumors. The ratio of ERα/ERβ expression is higher in breast tumors than in normal tissues, and ERα and ERβ are antagonistic to each other. ERα mediates the tumor-promoting effects of estrogens, whereas ERβ inhibits breast cancer cell growth. ERβ reduces cell proliferation induced by ERα activation. Although ERα and ERβ have been shown to have a yin-yang relationship in breast tumorige...

PES1 is overexpressed in Hepatocellular Carcinoma

“…Our previous results and other investigators' results showed that PES1 as a transcriptional factor could be recruited to the promotors of Cyclin D1 and heme oxygenase-1 genes and directly regulated the expressions of these genes [16,31]. Here we showed that PES1 changed the expression of genes related to cell cycle and angiogenesis such as Cyclin D1, p21WAF1, HIF1a and VEGF.…”

“…Previous researches showed that pescadillo was necessary in biogenesis of ribosome and played an essential role in cell proliferation and cell cycle [7][8][9][10][11][12][13][14]. It has been shown that pescadillo could immortalize or transform some kinds of mammalian cells [15,16]. Our previous researches and other investigators' researches showed that PES1 was overexpressed in many kinds of human cancer such as malignant astrocytomas and glioblastomas [6], breast cancer [16][17][18], prostatic cancer [19,20], head and neck squamous cell cancer [21], colon cancer [22], ovarian cancer [23], neuroblastoma [24] and gastric cancer [25].…”

“…It has been shown that pescadillo could immortalize or transform some kinds of mammalian cells [15,16]. Our previous researches and other investigators' researches showed that PES1 was overexpressed in many kinds of human cancer such as malignant astrocytomas and glioblastomas [6], breast cancer [16][17][18], prostatic cancer [19,20], head and neck squamous cell cancer [21], colon cancer [22], ovarian cancer [23], neuroblastoma [24] and gastric cancer [25]. These results suggest that PES1 may play an important role in tumor progression.…”

FHL1 inhibits the growth of tongue squamous cell carcinoma cells via G1/S cell cycle arrest

“…Anchorage-dependent cell proliferation was analyzed by crystal violet assay as described previously (14). For the anchorage-independent growth assay, cells (1x10 3 ) were seeded in a 12-well plate, with a bottom layer of 0.7% low-melting temperature agar in DMEM and a top layer of 0.35% agar in DMEM.…”

RETRACTED ARTICLE: Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy

“…Overexpression of CUEDC2 could contribute to this discordance. PES1 (also known as Pescadillo), an estrogen-inducible protein [166] …”