Low-density lipoprotein receptor mRNA in human breast cancer cells: Influence by PKC modulators

Abstract

It was reported previously that low-density lipoproteins (LDL) differentially stimulate cell growth of hormone-responsive (ER+) and hormone-unresponsive (ER-) mammary tumor cell lines. Here we examined the mRNA levels of the LDL-receptor (LDL-R) gene with RNAse protection analysis in ER- (MDA-MB-231 and HBL-100) and ER+ (MCF-7 and ZR75-1) cells, and compared them with the estrogen receptor (ER) status. Measurable amounts of ER mRNA were only found in ER+ cells as expected. LDL-R mRNA abundance was 3-5 fold higher in ER- cells as compared to ER+ cells. Incubation with phorbol-12-myristate-13-acetate led to a significant increase (p < 0.005) of LDL-R mRNA in ER+ cells, whereas in ER- cells LDL-R mRNA levels remained merely unchanged. Incubation of cells with dioctanoylglycerol, a synthetic homolog of diacylglycerol, increased LDL-R mRNA in ER+ but not in ER-. Inhibition of protein kinase C (PKC) by H7 resulted in a highly significant reduction of LDL-R mRNA both in ER+ and ER- cells. PKC seems to be an important regulator of LDL-R mRNA abundance in mammary tumor cells. It is hypothesized that in human-breast cancer the process of conversion from hormone-responsive to hormone-unresponsive status is accompanied by a change in PKC activity and PKC might exert cell specific differences on the regulation of LDL-R mRNA levels, which in turn influences the delivery of exogenous cholesterol to cancer cells.

Synthetic nano-low density lipoprotein as targeted drug delivery vehicle for glioblastoma multiforme

“…Increased LDL requirement and receptor activity has been observed in colon cancer (Niendorf et al, 1995), prostate tumors (Chen and Hughes-Fulford, 2001), adrenal tumors (Nakagawa et al, 1995), hormone unresponsive breast tumors (Stranzl et al, 1997), cancers of gynecological origin (Gal et al, 1981), lung tumor tissues (Vitols et al, 1992), leukemia (Tatidis et al, 2002, Vitols et al, 1994, Vitols et al, 1984, Ho et al, 1978, and malignant brain tumors (Rudling et al, 1990). It was previously suggested that plasma-derived LDL could be used as a drug delivery system for tumors expressing LDLR since its hydrophobic core has the possibility of incorporating lipophilic drugs (Firestone, 1994, Rensen et al, 2001.…”

Lipoproteins and Cancer

“…Although the role of SREBPs in feedback regulation of LDLR expression is well understood (Goldstein, DeBose-Boyd et al 2006), there is evidence that cell signaling pathways also contribute to LDLR up-regulation in cancer. In BrC cells, LDLR mRNA expression was 3-5-fold higher in ER-as compared to ER+ cell lines; PKC activation was strongly associated with increased LDLR expression in ER+ BrC cells, and to a lesser extent, even in ER-cells (Stranzl, Schmidt et al 1997). Activation of the p42/44 (MAPK) cascade was sufficient to induce LDLR transcription in human hepatoma HepG2 cells expressing oncogenic Raf-1 kinase (Kapoor, Atkins et al 2002).…”

The human breast carcinoma cell line HBL-100 acquires exogenous cholesterol from high-density lipoprotein via CLA-1 (CD-36 and LIMPII analogous 1)-mediated selective cholesteryl ester uptake

“…HBL-100 cells express the oestrogen and the LDL receptors [24]. Briefly, cells were grown in Dulbecco's modified Eagle's medium (DMEM) containing 10 % (v\v) fetal calf serum (FCS) or lipoproteindepleted serum (LPDS), 2 mM -glutamine, 100 units\ml penicillin and 100 mg\ml streptomycin.…”