Bile acids influence the growth, oestrogen receptor and oestrogen-regulated proteins of MCF-7 human breast cancer cells

Abstract

Summary The effects of the major human serum bile acid, glycochenodeoxycholic acid (GCDC), as well as unconjugated chenodeoxycholic acid (CDC), on the MCF-7 human breast cancer cell line have been studied in vitro under oestrogen and bile acid deprived culture conditions. GCDC increased the growth of the breast cancer cells over the range 10-300 jiM. At concentrations in excess of the bile acid binding capacity of the medium cell growth was prevented. In contrast 10 jiM CDC tended to reduce cell growth. Oestrogen (ER) and progesterone (PgR) receptors, pS2 and total cathepsin D were quantified by monoclonal antibody based immunoassays. Ten to 100 jiM GCDC and 10 jIM CDC down-regulated ER protein and this was accompanied by induction of the oestrogen-regulated proteins PgR, pS2 and possibly cathepsin D, including increased secretion of the latter two proteins into the culture medium. All these changes were quantitatively similar to those observed with 10 nm oestradiol. The bile acid effects on ER and PgR were not due to interference with the assay procedures. Cells incubated with 50 jIM GCDC or 10 jIM CDC had higher pmolar concentrations of the bile acids than controls. This study suggests that naturally occurring bile acids influence the growth and steroid receptor function of human breast cancer cells.Although bile acids have been considered to play a role in the aetiology and/or growth of colorectal cancer (Hill, 1983) little attention has been paid to the possible activity of these steroidal compounds in breast cancer. Epidemiological studies have demonstrated that rates of breast and colon cancers are highly correlated with each other and with high fat and animal protein diets (Drasar & Irving, 1973). In the few studies published the data suggest that women with breast cancer may have differences in the faecal excretion of bile acids compared with controls; decreased (Murray et al., 1980) and increased (Papatestas et al., 1982) faecal concentrations, and altered ratio of individual bile acids (Owen et al., 1986) have been reported. Long-term follow-up of women undergoing cholecystectomy has revealed an increased risk of breast cancer which increased with time after operation (Gudmundsson et al., 1989). In contrast, by reducing the enterohepatic circulation of oestrogens and bile acids, the high consumption of fibre and fermented milk products, particularly in combination with low fat and animal protein intake, may provide some protection against breast cancer (Adlercreutz, 1990). These findings, while by no means conclusive, imply that breast cancer patients are subject to changes in circulating levels of bile acids and consequently the potential exposure of breast tissue and/or tumour. In support of the latter possibility is our observation, now confirmed by others, that breast cyst fluid contains very high levels of bile acids, notably the glycine conjugates of chenodeoxycholic (CDC), deoxycholic and cholic acids (Baker et al., 1986 and1988a;Raju et al., 1990).Bile acids have been shown to produce DNA chan...

The E-screen assay: a comparison of different MCF7 cell stocks.

“…This increase was of the same order of magnitude as that described previously in monolayer cultures of MCF7 cells (5,(12)(13)(14)(15)(16).The other three cell stocks responded to estradiol-17f with a much smaller increase in cell yield, which was never higher than twofold over control values. Similar proliferative responses were reported in MCF7 cell stocks tested in media supplemented with different amounts of charcoal dextran serum, which ranged from 20% to 0.5% (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), and in serumless medium (31)(32)(33). Poor proliferative responses to estradiol-17t3 were described when nonstripped, serum-supplemented media were used (34)(35)(36).…”

“…In this stock, the hormone reduced estrogen receptor content, increased the amount of measurable progesterone receptor, and increased pS2 protein secretion. We found no significant effect of estradiol-179 on cathepsin-D protein synthesis (25). Although some MCF7 cell stocks respond to estradiol-17f3 with a higher increase in cathepsin-D protein secretion than others (46), all four MCF7 cell stocks tested here showed the same poor response.…”

“…The disparate effects of estradiol-17f1, other so-called mitogens, and growth inhibitors on cell proliferation have also been attributed to heterogeneity of the undoned cells (39,42,43) or to differences in the MCF7 cells used (8,13,16,25,44,45). The four cell stocks we assayed were cultured in the same medium (phenol red-free DME), which was suppleVolume 103, Number 9, September 1995 * Environmental Health Perspectives…”

Plasma deoxycholic acid concentration is elevated in postmenopausal women with newly diagnosed breast cancer

“…DCA is found in human breast cyst fluid at concentrations about 50 times greater than those in plasma (Raju et al, 1990;Javitt et al, 1994). DCA is mutagenic (Watabe & Bernstein, 1985), has a co-carcinogenic activity (Kawasumi et al, 1988) and promotes the growth, oestrogen receptor and oestrogen-regulated proteins of MCF-7 human breast cancer cells (Baker et al, 1992). The formation of DCA from CA in the colon is inhibited by low pH (van Munster et al, 1994).…”

The Farnesoid X Receptor Is Expressed in Breast Cancer and Regulates Apoptosis and Aromatase Expression

“…High levels of the plasma bile acid deoxycholic acid (DCA) are found in postmenopausal women newly diagnosed with breast cancer, whereas CDCA is present at high Amol/L levels in breast cyst fluid (23,24). Moreover, CDCA can inhibit the growth of the breast carcinoma cell line MCF-7, whereas glycol-CDCA causes proliferation (25). Here, we show the expression of FXR in normal breast ductal epithelial cells and in the cells of infiltrating ductal carcinoma of the breast.…”