Side-population cells in luminal-type breast cancer have tumour-initiating cell properties, and are regulated by HER2 expression and signalling.

Publisher: Nature Publishing Group on behalf of Cancer Research UK Country of Publication: England NLM ID: 0370635 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1532-1827 (Electronic) Linking ISSN: 00070920 NLM ISO Abbreviation: Br J Cancer Subsets: MEDLINE

Publication: 2002- : London : Nature Publishing Group on behalf of Cancer Research UK
Original Publication: London, Lewis.

ATP-Binding Cassette Transporters/*metabolism ; Breast Neoplasms/*metabolism ; Breast Neoplasms/*pathology ; Insulin-Like Growth Factor Binding Proteins/*metabolism ; Neoplasm Proteins/*metabolism ; Neoplastic Stem Cells/*pathology ; Receptor, ErbB-2/*metabolism; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; ATP-Binding Cassette Transporters/antagonists & inhibitors ; Animals ; Antibodies, Monoclonal/pharmacology ; Antibodies, Monoclonal, Humanized ; Blotting, Western ; Drug Resistance, Neoplasm ; Female ; Flow Cytometry ; Humans ; Insulin-Like Growth Factor Binding Proteins/antagonists & inhibitors ; Mice ; Mice, Inbred NOD ; Mice, Nude ; Mice, SCID ; Neoplasm Proteins/antagonists & inhibitors ; Proto-Oncogene Proteins c-akt/metabolism ; Receptor, ErbB-2/antagonists & inhibitors ; Signal Transduction ; Trastuzumab ; Tumor Cells, Cultured

Background: The expression of side-population (SP) cells and their relation to tumour-initiating cells (T-ICs) have been insufficiently studied in breast cancer (BC). We therefore evaluated primary cell cultures derived from patients and a panel of human BC cell lines with luminal- or basal-molecular signatures for the presence of SP and BC stem cell markers.
Methods: The SPs from luminal-type BC were analysed for BC T-IC characteristics, including human epidermal growth factor receptor 2 (HER2), ERalpha, IGFBP7 expression and their ability to initiate tumours in non-obese diabetic severe combined immunodeficiency (NOD/SCID) mice. Pharmacological modulators were used to assess the effects of HER2 signalling and breast cancer-resistance protein (BCRP) expression on SPs.
Results: The SP was more prevalent in the luminal subtype of BC compared with the basal subtype. HER2 expression was significantly correlated with the occurrence of an SP (r(2)=0.75, P=0.0003). Disappearance of SP in the presence of Ko143, a specific inhibitor of the ATP-binding cassette transporter BCRP, suggests that BCRP is the predominant transporter expressed in this population. The SP also decreased in the presence of HER2 signalling inhibitors AG825 or trastuzumab, strengthening the notion that HER2 contributed to the SP phenotype, likely through downstream AKT signalling. The SP cells from luminal-type MCF-7 cells with enforced expression of HER2, and primary cells with luminal-like properties from a BC patient, displayed enrichment in cells capable of repopulating tumours in NOD/SCID mice. Engraftment of SP cells was inhibited by pretreatment with AG825 or by in vivo treatment with trastuzumab.
Interpretation: Our findings indicate an important role of HER2 in regulating SP and hence T-ICs in BC, which may account for the poor responsiveness of HER2-positive BCs to chemotherapy, as well as their aggressiveness.

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0 (ABCG2 protein, human)
0 (ATP Binding Cassette Transporter, Subfamily G, Member 2)
0 (ATP-Binding Cassette Transporters)
0 (Antibodies, Monoclonal)
0 (Antibodies, Monoclonal, Humanized)
0 (Insulin-Like Growth Factor Binding Proteins)
0 (Neoplasm Proteins)
0 (insulin-like growth factor binding protein-related protein 1)
EC 2.7.10.1 (ERBB2 protein, human)
EC 2.7.10.1 (Receptor, ErbB-2)
EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
P188ANX8CK (Trastuzumab)

Date Created: 20100211 Date Completed: 20100401 Latest Revision: 20240404

20250114

PMC2833247

10.1038/sj.bjc.6605553

20145614