Aberrant expression of LMO4 induces centrosome amplification and mitotic spindle abnormalities in breast cancer cells

Abstract

The LIM-only protein, LMO4, is a transcriptional modulator overexpressed in breast cancer. It is oncogenic in murine mammary epithelium and required for G2/M progression of ErbB2-dependent cells as well as growth and invasion of other breast cancer cell types. However, the mechanisms underlying the oncogenic activity of LMO4 remain unclear. Herein, we show that LMO4 is expressed in all breast cancer subtypes examined and its expression level correlates with the degree of proliferation of such tumors. In addition, we have determined that LMO4 silencing induces G2/M arrest in cells from various breast cancer subtypes, suggesting LMO4 action in the cell cycle is not restricted to a single breast cancer subtype. This arrest was accompanied by increased cell death, amplification of centrosomes and formation of abnormal mitotic spindles. Consistent with its ability to positively and negatively regulate the formation of active transcription complexes, overexpression of LMO4 also resulted in an increase in centrosome number. Centrosome amplification has been shown to prolong the G2/M phase of the cell cycle and induce apoptosis, thus we conclude that supernumerary centrosomes mediate the G2/M arrest and cell death in LMO4-deficient cells. Furthermore, the correlation of centrosome amplification with genomic instability suggests that the impact of dysregulated LMO4 on the centrosome cycle may promote LMO4-induced tumor formation.

Long non‑coding RNA SNHG1 promotes breast cancer progression by regulation of LMO4

“…LIM domain only 4 (LMO4) expression is frequently elevated in breast cancer (34). Additional experiments in breast cancer cells from various subtypes demonstrated that LMO4 induced cyclin D1 and cyclin E1 expression to promote cell cycle progression and facilitate cell proliferation (35). The expression of LMO4 was regulated by miR-409-3p in colorectal cancer (50).…”

“…6A). LMO4 is a transcription factor that activates cyclin D1 and E1 transcription and mediates cell cycle progression (35). Knockdown of SNHG1 reduced cyclin D1 and cyclin E1 mRNA levels (Fig.…”

The oncoprotein HBXIP activates transcriptional coregulatory protein LMO4 via Sp1 to promote proliferation of breast cancer cells

“…It has been reported that LMO4 plays a crucial role in the centrosome cycle as well as cell cycle progression in breast cancer cells. It can regulate several cell cycle-related genes, including cyclin D1, cyclin E, p21, p27 and BRCA1 (11,18). Strikingly, growing evidence indicates that LMO4 can modulate progression of breast cancer cell cycle by indirectly enhancing the expression of G 1 cyclins, such as cyclin D1 and cyclin E, and contributes to the growth of multiple breast cancer cells (19–21).…”

LMO4 inhibits p53-mediated proliferative inhibition of breast cancer cells through interacting p53

“…Recently, it was reported that LMO4 is a downstream target of ERBB-2 and its signaling protein PI3K and is essential for ERBB2-mediated proliferation and cell cycle progression in ERBB-2-dependent breast cancer cells (Montañez-Wiscovich et al, 2009). Pathological results also showed that the aberrant expression of LMO4 on the centrosome cycle promoted LMO4-induced breast cancer formation (Montañez-Wiscovich et al, 2010). Increasing evidence suggested that the LIM domain of LMO4 protein acted as a docking site for the assembly of multiprotein complexes including HEN1 (Manetopoulos et al, 2003), CtBP-interacting protein and BRCA1 complex (Sum et al, 2002), ERα and MTA1 complex (Singh et al, 2005), Clim-2/ldb-1/Nl1 (Sugihara et al, 1998), DEAF1 (Hahm et al, 2004), peroxisome proliferation-activated receptor-γ (PPARγ) (Schock et al, 2008), cAMP response element-binding protein (CREB) complex (Kashani et al, 2006), glycoprotein 130 complex (Novotny-Diermayr et al, 2005), and transcription modulator Cited2 (Michell et al, 2010), which provided further compelling evidence for LMO4 playing a significant role in cells.…”