Abstract
IntroductionExogenous prolactin is mitogenic and antiapoptotic in breast cancer cells, and overexpression of autocrine prolactin cDNA in breast cancer cell lines has been shown to stimulate their growth and to protect against chemotherapy-induced apoptosis. We examined the effects of the 'pure' prolactin receptor antagonist Δ1–9-G129R-hPrl (Δ1–9) on the breast cancer cell number and clonogenicity, alone and in combination with chemotherapy.MethodsThe effects of doxorubicin, paclitaxel and Δ1–9 on the growth of breast cancer cell lines (MCF-7, T47D, MDA-MB-453, MDA-MB-468 and SK-BR-3) in monolayer culture were assessed by the sulphorhodamine B assay. Effects on clonogenicity were assessed by soft agar assay for the cell lines and by the mammosphere assay for disaggregated primary ductal carcinoma in situ samples. Dual-fluorescence immunocytochemistry was used to identify subpopulations of cells expressing the prolactin receptor and autocrine prolactin.ResultsΔ1–9 as a single agent had no effect on the cell number in monolayer culture, but potentiated the cytotoxic effects of doxorubicin and paclitaxel. Doxorubicin accordingly induced expression of prolactin mRNA and protein in all five breast cancer cell lines tested. Δ1–9 alone inhibited the clonogenicity in soft agar of cell lines by ~90% and the mammosphere forming efficiency of six disaggregated primary ductal carcinoma in situ samples by a median of 56% (range 32% to 88%). Subpopulations of cells could be identified in the cell lines based on the prolactin receptor and prolactin expression.ConclusionAutocrine prolactin appears to act as an inducible survival factor in a clonogenic subpopulation of breast cancer cells. The rational combination of cytotoxics and Δ1–9 may therefore improve outcomes in breast cancer therapy by targeting this cell population.
Highlights
Exogenous prolactin is mitogenic and antiapoptotic in breast cancer cells, and overexpression of autocrine prolactin cDNA in breast cancer cell lines has been shown to stimulate their growth and to protect against chemotherapy-induced apoptosis
Δ1–9 alone inhibited the clonogenicity in soft agar of cell lines by ~90% and the mammosphere forming efficiency of six disaggregated primary ductal carcinoma in situ samples by a median of 56%
Autocrine prolactin appears to act as an inducible survival factor in a clonogenic subpopulation of breast cancer cells
Summary
Exogenous prolactin is mitogenic and antiapoptotic in breast cancer cells, and overexpression of autocrine prolactin cDNA in breast cancer cell lines has been shown to stimulate their growth and to protect against chemotherapy-induced apoptosis. Exogenous prolactin has been shown to induce the proliferation, survival, migration and invasion of breast cancer cell lines in vitro and to increase the clonogenicity of primary human breast cancer samples in soft agar [1,2,3,4,5]. The majority of human breast cancers have been shown to express the prolactin receptor (PRLR) [11] Despite these observations, attempts to treat advanced breast cancer through the pharmacological inhibition of pituitary prolactin secretion, either as monotherapy or in combination with tamoxifen, have been disappointing. In a recent study of women with metastatic breast cancer, a significant increase in the objective tumour response rate was seen when the dopamine agonist cabergoline was added to docetaxel versus treatment with docetaxel alone
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