Increased phospholipase D activity in human breast cancer

Abstract

Phospholipase D is believed to play an important role in cell proliferation and tumorigenesis. One of its major functions is to cause a sustained activation of protein kinase C through the primary production of phosphatidic acid from phosphatidylcholine by the enzyme, followed by dephosphorylation forming diacylglycerol. Protein kinase C is known to be activated or translocated in some tumors including breast tumors. In order to examine phospholipase D activity in breast tumors, surgical specimens of human breast tumors were obtained by mastectomy or wide excision, and their phospholipase D activities were assayed by determining the formation of phosphatidylethanol from phosphatidylcholine and ethanol. Phospholipase D activity was predominantly localized in the microsomal fraction of the tumor tissue and markedly stimulated by oleic acid. We observed a significant increase in phospholipase D activity in 17 out of 19 spontaneous human breast tumors as compared to adjacent histologically normal breast tissue. The mean specific activity in the tumors was 52.9 +/- 41.8 (SD) pmol min-1 mg protein-1 whereas the value for the normal breast tissue was 34.0 +/- 36.2 (SD) pmol min-1 mg protein-1 (P < 0.01; paired Wilcoxon's rank-sum test). The mean tumor/normal activity ratio was 2.37. Among prognostic factors, the nuclear grade, evaluated according to Schnitt et al., was found to be correlated with the activity ratio. Our results suggest a role for phospholipase D in human breast tumors. An elevation in phospholipase D activity is useful as a potential marker for malignant disease in the breast.

Alternative phospholipase D/mTOR survival signal in human breast cancer cells

“…Thus, evidence supporting a role for PLD in regulating both growth factor-and oncogene-induced cell proliferation is substantial. And, consistent with this hypothesis, elevated expression of PLD1 has been reported to be common in breast cancer tissues (Uchida et al, 1997;Noh et al, 2000). PLD activity has also been reported to be elevated in renal (Zhao et al, 2000) and gastric (Uchida et al, 1999) cancers and a polymorphism of the PLD2 gene was recently reported to be associated with the prevalence of colorectal cancer (Yamada et al, 2003).…”

Autoregulation of phospholipase D activity is coupled to selective induction of phospholipase D1 expression to promote invasion of breast cancer cells

“…Participation of PLD-generated PA in downstream signal transduction from mitogenic growth factor receptors via Ras and the MAP kinase pathway has been demonstrated. 12 In comparison with adjacent non-neoplastic tissues, elevated expression and activity of PLD have been detected in various human tumors, including those of breast, 7,31 colorectal, 32,33 gastric, 34 renal 35 and papillary thyroid cancers. 36 Recent clinical studies have reported on correlation of PLD expression levels with tumor size; an association with survival of patients with colorectal carcinoma was also reported.…”

“…Endogenous levels of PA are low in resting cells, and PLD activity is tightly regulated by mechanisms that control secretion, migration, survival and proliferation of cells. 1,2 PLD is activated by a variety of mitogens, including epidermal growth factor (EGF), platelet-derived growth factor (PDGF) and interleukin 1b (IL-1b), [3][4][5][6][7] and its involvement in many cellular biological processes, including cell proliferation, survival, vesicular trafficking and secretion, has been demonstrated. 1,8 Two distinct isoforms of mammalian PLD, PLD1 and PLD2, have been identified.…”

The phospholipid code: a key component of dying cell recognition, tumor progression and host–microbe interactions

“…61 Phospholipase D overexpression has been reported for many cancer types including breast cancer cell lines and tissue samples, as well as renal and gastric cancers and is associated with mTOR-mediated pro-survival phenotypes. [62][63][64][65] Thus, modification of the intracellular phospholipid code by changes in the expression and/or activity of various phospholipid modifiers can ultimately regulate tumor progression.…”