Phosphomonoester is associated with proliferation in human breast cancer: a 31P MRS study

Abstract

Summary Phospholipid metabolism of human breast cancer was studied by 31p magnetic resonance spectroscopy (MRS). In vivo localised 31p MR spectra were obtained from the tumour alone using phase modulated rotating frame imaging. For 31 tumours, median (range) phosphomonoester (PME) to ATP ratio was 1.48 (0.57-3.78) and phosphodiester (PDE) to ATP ratio was 1.65 (0.44-3.89). DNA index and S phase fraction (SPF) were measured by flow cytometry of paraffin embedded tissue. Twelve (39%) tumours were diploid and 19 aneuploid. Median (range) SPF for 29 assessable tumours was 5.3% (0.6-28%), with significantly greater median SPF for aneuploid tumours (9.3%) than diploid (3.8%, P = 0.007). There was a significant association between PME/ATP and SPF (P= 0.03) due to a significant correlation for aneuploid tumours (P= 0.01). High resolution 31P MRS of extracts from 18 tumours (including seven studied in vivo) demonstrated that the PME peak consists predominantly of phosphoethanolamine (PE) with a smaller contribution from phosphocholine (PC) (median (range) PE/PC: 3.02 (1.13-5.09)). Changes in PME/ATP were observed for two tumours where tamoxifen stablised disease and may be consistent with the cytostatic effects of this drug.Breast cancer is the commonest cancer in women with an annual mortality rate in the United Kingdom of over 14,000 (OPCS Monitor, 1992), and its incidence appears to be rising in the western hemisphere (Glass & Hoover, 1990). Reduction in mortality has been reported for mammographic screening (Shapiro et al., 1982;Tabar et al., 1985) and adjuvant chemotherapy (Early Breast Cancer Trialists' Collaborative Group, 1992a,b (Glaholm et al., 1989). In another report of three patients with locally advanced breast tumours, PME/ATP decreased in response to therapy (Ng et al., 1989). PC and PE are intermediates in membrane phospholipid biosynthesis and can also be generated by growth factor signalling (Fisher et al., 1991). The concentration of PME may reflect the rate of cell membrane synthesis and therefore cellular proliferation . This is consistent with the observation of high concentration of the phosphomonoester, PE in the developing infant brain (Hope et al., 1984;Younkin et al., 1984) and liver (Moorcroft et al., 1991), and is further supported by the increase in PME to ATP ratio during liver regeneration in the rat following 70% resection (Murphy et al., 1992). However, alteration in PME associated with therapy could also be explained by a change in cellular number, particularly as in most cases there was an associated change in tumour size. The biochemical basis for therapy induced changes in PME in human breast cancer detected by 31p MRS is not clear.The aim of this study was to assess the relationship between the level of PME measured by 31P MRS in vivo and proliferation in untreated, primary human breast cancer. Patients were studied the day before surgery using 31P MRS and where possible, PME composition of extracts of tumour were studied by high resolution 31P MRS to aid interpretation of the in...

Wortmannin inhibits carcinogen‐stimulated phosphorylation of ethanolamine and choline

“…After a 3 h labeling period, a preceding DMBA treatment for 24 h enhanced the phosphorylation of however, it is clear that at least in fibroblasts, a longer exposure to the carcinogen preferentially enhances the cellular level of EtnP, even though the activated kinase phosphorylates both Etn and Cho. This may be relevant to other observations indicating that in several human tumors it is EtnP, and not ChoP, whose tissue level is enhanced [9][10][11][12][13][14][15]. The second major finding of this work was that wortmannin, an inhibitor of PI3K [7], also inhibited phosphorylation of both Cho and Etn.…”

An inbred colony of oncogene transgenic mice: diversity of tumours and potential as a therapeutic model

“…The median S-phase fraction value for murine mammary carcinomas arising in this colony is similar to that of human mammary carcinomas (9.0% in these tumours; 9.6% in humans) (Camplejohn et al, 1995). A higher proportion of the murine tumours were aneuploid than in many human series (11/12 in this study as compared with 18/29 human tumours in Kalra et al (1993)) but this is entirely consistent with the poor differentiation of these tumours, and characteristic of their neu positivity.…”

“…They appear to have a relatively low incidence of spontaneous mammary tumours (up to 5% in retired breeding females) (Foster et al, 1982). Other sources suggest up to 3% in breeding females and 1% in virgin mice (Smith and Pilgrim, 1971;Kalra et al, 1993) during the normal lifespan of the mouse. The incidence of spontaneous lymphomas in BALB/c mice kept in germ-free conditions is less than 3% but again the overexpression of neu suggests that the transgene is involved.…”

Ha‐Ras stimulates uptake and phosphorylation of ethanolamine: inhibition by wortmannin

“…The results indicating that wortmannin inhibited only the phosphorylation of externally added Etn, but not of Etn formed endogenously from PtdEtn, strongly suggest that PI3K, activated by mutated Ras [13], positively regulates Etn transport. Many human cancers are characterized by increased levels of EtnP, but not ChoP [21][22][23][24][25][26][27]. This suggests that aggressive growth of certain cancers requires high levels of EtnP, which is achieved through the stimulation of both uptake and phosphorylation of Etn.…”