The developmental protein HOXc11 as a mediator of endocrine resistance in breast cancer.

Abstract

Abstract Abstract #3034 The nuclear receptor coactivator, SRC-1, has been implicated as an important mediator of resistance to endocrine therapy in breast cancer through work from our group and others. Using mass spectrometry we identified the homeobox protein HOXc11 as an interacting partner for the nuclear receptor coactivator SRC-1 in endocrine resistant breast cancer cells. Homeobox genes control cell differentiation. The processes of neoplasia and normal development are closely linked, therefore it is little surprise that increasing evidence implicates these genes in neoplasia development.
 We propose that the interaction between SRC-1 and HOXc11 plays an important role in the development of endocrine resistance. Our aim was to identify potential HOXc11/SRC-1 target genes and assess the clinical significance of these genes.
 Co-immunprecipitation assays confirmed the SRC-1 and HOXc11 interaction after treatment with tamoxifen for 2 hours in the endocrine resistant LY2 breast cancer cell line, an interaction that was not present in endocrine sensitive MCF-7 cells under the same treatment conditions. A target gene for HOXc11, S100β, has previously been identified in neuronal cells. Based on this we sought the presence of either protein at the promoter region for S100β. Chromatin immunoprecipitation (ChIP) assays in LY2 cells confirmed recruitment of both HOXc11 and SRC-1 to the promoter region of S100β after treatment with tamoxifen at both 45 minutes and 2 hours when compared to control.
 To assess the clinical significance of S100β, we used immunohistochemistry on a paraffin embedded tissue microarray to examine itÂs expression in a large cohort of breast cancer patients (n=560). S100β was a strong predictor of reduced disease free survival in patients receiving adjuvant endocrine treatment (Hazard ratio 5.82; p<0.0001). This also showed that expression of S100β was associated with expression of HOXc11 and SRC-1. Given that S100β is a secreted protein, we hypothesized that elevated levels could be detected in patients with breast cancer at time of diagnosis. Using an ELISA to measure S100β levels, we found elevated levels in one quarter of breast cancer patients, pre treatment, when compared to age matched controls.
 Investigation into non steroidal SRC-1 binding partners in endocrine resistant breast cancer identified the homeobox protein HOXc11. A target gene for the interaction between SRC-1 and HOXc11, S100β, is a secreted protein and raises the exciting possibility that it may offer potential as a biomarker for endocrine resistance in breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3034.