Repression of Lim only protein 4-activated transcription inhibits proliferation and induces apoptosis of normal mammary epithelial cells and breast cancer cells

Abstract

Lim only protein (LMO) 4 acts as a transcriptional adapter and modulates mammary gland morphogenesis as well as breast oncogenesis in transgenic mice. Yet, the molecular and cellular mechanisms of these effects remain to be fully elucidated. Engrailed LMO4 fusion protein is a powerful dominant repressor of LMO4 activated transcription that was successfully used to discover the role of LMO4 as a transcriptional activator in mammary gland development in our previous studies using mouse models. In this manuscript, we investigated the cellular effects of LMO4 in human normal mammary epithelial cells (HMECs) and breast cancer cell lines using the Engrailed-LMO4 fusion protein. HMEC cell growth was inhibited by the expression of the Engrailed-LMO4 fusion protein. The decrease in cell number was due to both decreased cell proliferation and enhanced apoptosis, suggesting that LMO4 promotes proliferation and survival of normal mammary epithelial cells. The expression of the Engrailed-LMO4 fusion protein also suppressed cell growth, and induced apoptosis in two breast cancer cell lines, MDA-MB-231 and T47D, suggesting that LMO4 contributes to oncogenesis by similar mechanisms of enhanced cell survival and proliferation. Taken together, our data indicate that LMO4 has similar cellular effects in normal mammary epithelial cells and breast cancer cells, and also provide direct evidence for the idea that normal development and carcinogenesis share conserved molecular mechanisms.

Targeting nitrative stress for attenuating cisplatin-induced downregulation of cochlear LIM domain only 4 and ototoxicity

“…This was also supported by the increase in the number of condensed nuclei in LMO4 deficient cells relative to wild-type cells treated with cisplatin. These findings suggested that in the absence of LMO4 the susceptibility of the inner ear cells to cisplatin-induced toxicity is significantly enhanced and is consistent with other reports, which indicate repression of LMO4 promotes apoptosis [37]. The viability of UBOC1 cells treated with scrambled RNA was similar to that of the control cells.…”

“…Consistent with these reports, cisplatin-induced nitration of LMO4 was associated with a significant decrease in its protein levels, not only in the auditory cells, but in the renal and neuronal cells, which are also susceptible to the toxic side-effects of cisplatin [35]. Repression of LMO4 has been reported to facilitate cellular apoptosis in other models [36], [37].…”

In Silico Analysis Guides Selection of BET Inhibitors for Triple-Negative Breast Cancer Treatment

“…The most significant and maintained reduction were observed for the following genes: DEP domain containing 1 (DEPDC), Forkhead box M1 (FOXM1), and Lim domain only 4 (LM04). Although the expression of these genes has been associated with carcinogenesis in different tumor models, little has been described in breast cancer and particularly in TNBC (22)(23)(24)(25)(26).…”

LMO4 is a prognostic marker involved in cell migration and invasion in non-small-cell lung cancer

“…Therefore, LMO4 silencing reduces tumor cell proliferation and induces aG2/M arrest associated with decreased cullin-3, an E3-ubiquitin ligase component important for mitosis (16). LMO4 can inhibit the expression of the fusion proteinengrailed-LMO4 while suppressing cell growth, and can induce the apoptosis of breast cancer cells, indicating that LMO4 contributes to oncogenesis by similar mechanisms, thus enhancing cell survival and proliferation (19). AKT/PI3K activation is involved in the carcinogenesis and tumor progression of various solid tumors, including NSCLC (20,21).…”