ACSL4: biomarker, mediator and target in quadruple negative breast cancer.

Breast cancer is a heterogeneous disease for which effective treatment depends on correct categorization of its molecular subtype. For the last several decades this determination has relied on hormone receptor status for estrogen, progesterone and HER2. More recently, gene expression data have been generated that further stratify both receptor-positive and receptor-negative cancers.

Fatty acid metabolism in breast cancer subtypes.

Dysregulation of fatty acid metabolism is recognized as a component of malignant transformation in many different cancers, including breast; yet the potential for targeting this pathway for prevention and/or treatment of cancer remains unrealized. Evidence indicates that proteins involved in both synthesis and oxidation of fatty acids play a pivotal role in the proliferation, migration and invasion of breast cancer cells. The following essay summarizes data implicating specific fatty acid metabolic enzymes in the genesis and progression of breast cancer, and further categorizes the relevance of specific metabolic pathways to individual intrinsic molecular subtypes of breast cancer.

Breast cancer molecular subtypes: from TNBC to QNBC.

Treatment protocols for breast cancer depend predominantly on receptor status with respect to estrogen (estrogen receptor alpha), progesterone (progesterone receptor) and human epidermal growth factor [human epidermal growth factor receptor 2 (HER2)]. The presence of one or more of these receptors suggests that a treatment targeting these pathways might be effective, while the absence of, or in the case of HER2, lack of overexpression of, all of these receptors, termed triple negative breast cancer (TNBC), indicates a need for the more toxic chemotherapy. In an effort to develop targeted therapies for TNBC, it will be necessary to differentiate among specific TNBC subtypes.

ACSL4 promotes prostate cancer growth, invasion and hormonal resistance.

Increases in fatty acid metabolism have been demonstrated to promote the growth and survival of a variety of cancers, including prostate cancer (PCa). Here, we examine the expression and function of the fatty acid activating enzyme, long-chain fatty acyl-CoA synthetase 4 (ACSL4), in PCa. Ectopic expression of ACSL4 in ACSL4-negative PCa cells increases proliferation, migration and invasion, while ablation of ACSL4 in PCa cells expressing endogenous ACSL4 reduces cell proliferation, migration and invasion.

Lipid metabolism in prostate cancer.

The malignant transformation of cells requires adaptations across multiple metabolic processes to satisfy the energy required for their increased rate of proliferation. Dysregulation of lipid metabolism has been a hallmark of the malignant phenotype; increased lipid accumulation secondary to changes in the levels of a variety of lipid metabolic enzymes has been documented in a variety of tumors, including prostate. Alterations in prostate lipid metabolism include upregulation of several lipogenic enzymes as well as of enzymes that function to oxidize fatty acids as an energy source.

Long chain fatty Acyl-CoA synthetase 4 is a biomarker for and mediator of hormone resistance in human breast cancer.

The purpose of this study was to determine the role of long-chain fatty acyl-CoA synthetase 4 (ACSL4) in breast cancer. Public databases were utilized to analyze the relationship between ACSL4 mRNA expression and the presence of steroid hormone and human epidermal growth factor receptor 2 (HER2) in both breast cancer cell lines and tissue samples. In addition, cell lines were utilized to assess the consequences of either increased or decreased levels of ACSL4 expression.

LEF1 identifies androgen-independent epithelium in the developing prostate.

Lymphoid enhancer-binding factor (LEF)1 is a major mediator and a target in canonical Wnt/β-catenin pathway. Interactions between the androgen receptor (AR) and canonical Wnt pathways have been implicated in the development of the genitourinary organs. Here, we investigated the localization and role of LEF1-positive cells during development of the prostate gland in human and in the murine model.

Expression of Long-chain Fatty Acyl-CoA Synthetase 4 in Breast and Prostate Cancers Is Associated with Sex Steroid Hormone Receptor Negativity.

Previous studies have shown that key enzymes involved in lipid metabolic pathways are differentially expressed in normal compared with tumor tissues. However, the precise role played by dysregulated expression of lipid metabolic enzymes and altered lipid homeostasis in carcinogenesis remains to be established. Fatty acid synthase is overexpressed in a variety of cancers, including breast and prostate.

Subcellular localization of phosphatidylinositol synthesis.

It is well-established that the endoplasmic reticulum is the major site of phosphatidylinositol (PtdIns) synthesis. The PtdIns synthetic ability of other organelles, such as plasma membrane and nucleus, remains controversial. In the present study, we re-examine this question by comparing PtdIns synthesis in isolated cytoplasts (enucleated cells) with that in corresponding karyoplasts (nuclei surrounded by plasma membrane but lacking most cytoplasmic components).

Regulation of de novo phosphatidylinositol synthesis.

Mechanisms that function to regulate the rate of de novo phosphatidylinositol (PtdIns) synthesis in mammalian cells have not been elucidated. In this study, we characterize the effect of phorbol ester treatment on de novo PtdIns synthesis in C3A human hepatoma cells. Incubation of cells with 12-O-tetradecanoyl phorbol 13-acetate (TPA) initially (1-6 h) results in a decrease in precursor incorporation into PtdIns; however, at later times (18-24 h), a marked increase is observed.

SOM230 inhibits insulin-like growth factor-I action in mammary gland development by pituitary independent mechanism: mediated through somatostatin subtype receptor 3?

Somatostatin analogs (SAs) treat acromegaly by lowering pituitary GH secretion, which, in turn, lowers systemic IGF-I. The profound systemic effect is often greater than expected in the face of only partial GH suppression. Here we report that the SA SOM230 can also act by a nonpituitary-mediated inhibition of IGF-I action.

Progesterone stimulates mammary gland ductal morphogenesis by synergizing with and enhancing insulin-like growth factor-I action.

Progestins have been implicated in breast cancer development, yet a role for progesterone (Pg) in ductal morphogenesis (DM) has not been established. To determine whether Pg could cause DM, we compared relative effects of Pg, estradiol (E2) and IGF-I on anatomical and molecular biological parameters of IGF-I-related DM in oophorectomized female IGF-I(-/-) mice. Pg had little independent effect on mammary development, but together with IGF-I, in the absence of E2, Pg stimulated an extensive network of branching ducts, occupying 92% of the gland vs.

Lipid metabolism in phosphatidylinositol transfer protein alpha-deficient vibrator mice.

Mice that are homozygous for the vibrator mutation express 65-85% less phosphatidylinositol transfer protein alpha (PITPalpha) than their wild type litter mates. By postnatal day 10-12 (P10-12) they exhibit signs of neurodegeneration and die prematurely by P40. In the present study, we examine the lipid content of brain, liver, and mammary glands from these animals.

Analysis of hormone-stimulated phosphatidylinositol synthesis.

Agonist-stimulated phosphoinositide turnover is accompanied by compensatory resynthesis of these lipids. Several lines of evidence suggest that resynthesis of phosphatidylinositol (PtdIns) involves phosphorylation of diacylglycerol (DG) (salvage pathway) rather than acylation of glycerol phosphate (de novo pathway), although a contribution from the de novo pathway has not been ruled out. To determine the relative contribution of the de novo and salvage pathways in stimulated PtdIns resynthesis, an inhibitor of de novo synthesis (Triacsin C) was incubated simultaneously with the hormone agonist.