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- DOI: 10.1186/bcr2129
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Prolactin receptor antagonism reduces the clonogenic capacity of breast cancer cells and potentiates doxorubicin and paclitaxel cytotoxicity.
Howell SJ, Anderson E, Hunter T, Farnie G, Clarke RB
Breast Cancer Res. 2008;10( 4).
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Full-text held externally
- DOI: 10.1186/bcr2129
Abstract
ABSTRACT: INTRODUCTION: Exogenous prolactin is mitogenic and antiapoptotic in breast cancer cells and over-expression of autocrine prolactin cDNA in breast cancer cell lines has been shown to stimulate their growth and protect against chemotherapy induced apoptosis. We examined the effects of the 'pure' prolactin receptor (PRLR) antagonist Delta1-9-G129R-hPrl (Delta1-9) on breast cancer cell cell number and clonogenicity, alone and in combination with chemotherapy. METHODS: The effects of doxorubicin, paclitaxel and Delta1-9 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 sulphorhodamine B (SRB) assay. Effects on clonogenicity were assessed by soft agar assay for the cell lines and the mammosphere assay for disaggregated primary ductal carcinoma in situ (DCIS) samples. Dual fluorescence immunocytochemistry was used to identify subpopulations of cells expressing the PRLR and autocrine prolactin. RESULTS: Delta1-9 as a single agent had no effect on cell number in monolayer culture, but potentiated the cytotoxic effects of doxorubicin and paclitaxel. Accordingly doxorubicin induced expression of prolactin mRNA and protein in all 5 breast cancer cell lines tested. Delta1-9 alone inhibited the clonogenicity in soft agar of cell lines by ~90% and of mammosphere forming efficiency of six disaggregated primary DCIS samples by a median of 56% (range 32 to 88%). Subpopulations of cells could be identified in the cell lines based on PRLR and prolactin expression. CONCLUSIONS: Autocrine prolactin appears to act as an inducible survival factor in a clonogenic sub-population of breast cancer cells. Thus the rational combination of cytotoxics and Delta1-9 may improve outcomes in breast cancer therapy by targeting this cell population.