Parathyroid hormone-related protein secretion is inhibited by oestradiol and stimulated by antioestrogens in KPL-3C human breast cancer cells

Abstract

Summary We recently established a human breast cancer cell line, KPL-3C, from a breast cancer patient with humoral hypercalcaemia. This cell line possesses oestrogen receptor (ER) and secretes parathyroid hormone-related protein (PTHrP) into medium. To investigate the effects of oestrogen and antioestrogens on PTHrP secretion, KPL-3C cells were cultured for 48 h in an oestrogen-eliminated medium with 17,B-oestradiol (E2), tamoxifen (TAM) and/or a pure antioestrogen, IC1182,780 (ICI), and PTHrP secretion was measured using an immunoradiometric assay. The effects of these agents on cell cycle progression were also studied using flow cytometry. E2 (1-100 nM) significantly inhibited PTHrP secretion, whereas both TAM (0.1-10 gM) and ICI (1-100 nM) significantly stimulated it. These effects were completely blocked by the simultaneous addition of 1 nM E2 to the medium. At the same time, E2 significantly increased the percentage of cells during the S and G/M phases, whereas both antioestrogens significantly increased the percentage of cells during the GO/G1 phase. Again, these cytostatic effects were completely reversed by the addition of E2. These findings indicate that antioestrogens inhibit the growth of ERpositive breast cancer cells but may stimulate PTHrP secretion and that these effects may be mediated by ER.

Temporally regulated overexpression of parathyroid hormone-related protein in the mammary gland reveals distinct fetal and pubertal phenotypes

“…If PTHrP does act in a negative feedback loop to restrain the proliferative effects of estrogen, one might expect that expression of PTHrP or its receptor would be modified by estrogen. Although estrogen has been reported to upregulate, downregulate or not change the concentrations of PTHrP in breast cancer cell lines (Kurebayashi & Sonoo 1997, Funk & Wei 1998, Sugimoto et al 1999, we have found no evidence that hormone treatment affects levels of whole gland PTHrP or PTH-1R mRNA in early adolescent mice (unpublished results). However, it has been reported that the production of PTHrP by normal mammary epithelial cells in culture is enhanced by treatment with either EGF or TGF- (Ferrari et al 1992, 1994, Sebag et al 1994, Yin et al 1999.…”

Characterisation of ligand binding to the parathyroid hormone/parathyroid hormone‐related peptide receptor in MCF7 breast cancer cells and SaOS‐2 osteosarcoma cells

“…18 In contrast, when ROS 17/2.8 cells were treated with DEX for 6 and 24 h, the specific binding of 125 I-PTHrP-1-36 was increased, but when the same cells were treated with progesterone the effect of DEX on PTH/PTHrP-R expression was diminished. 19 There are some comparable data from KPL-3C and MCF7 cell lines on the effect of phorbol ester, steroid hormones, anti-estrogens and extracellular matrix (ECM) [26][27][28][29] but no reports on the effects of EGF, 1,25DHCC and DEX on PTH/PTHrP-R protein or gene expression in breast cancer cells. Nevertheless the data here suggest an additional mechanism by which the use of vitamin D analogues may act to suppress the proliferation of breast cancer cells.…”

Extracellular matrix regulation of PTHrP and PTH/PTHrP receptor in a human breast cancer cell line

“…We have already demonstrated the in vitro anti‐proliferative and pro‐invasive effect exerted on the carcinoma cell line 8701‐BC and some derived clones by PTHrP [11,12], which has been therefore regarded also as one of the key elements potentially involved in mammary tumorigenesis in vivo. Nonetheless, the regulation of PTHrP and PTHrP‐R expression and iPTHrP secretion by breast cancer cells has been poorly investigated, the unique data being those regarding the effect of phorbol ester, steroid hormones and anti‐estrogens on KPL‐3C and MCF7 cell lines [33–35].…”