Novel non-steroidal p160 coactivator interactions in tamoxifen resistant breast cancer.

Abstract

Abstract Abstract #3038 While most breast cancer patients initially respond to endocrine therapy, 30-40% of cases relapse within 5 years of treatment. Translational studies from our group and others have provided substantial evidence of a significant role for p160 family of Steroid Receptor Co-activator (SRC) proteins in the development of resistance to endocrine therapy. In this study we have investigated novel non-steroidal SRC-1 interactions in endocrine resistant breast cancer.
 A mass-spectrometry-based screen was used to identify proteins which differentially interact with SRC-1 in endocrine resistant compared with endocrine sensitive breast cancer cells. The developmental protein, HOXC11, was confirmed as an SRC-1 interacting partner. HOXC11 was shown to be over-expressed in tamoxifen-resistant cells using immunocytochemistry and was observed to translocate to the nucleus and peri-nuclear region when cells were treated with tamoxifen. In a breast cancer TMA (n=560) HOXC11 was found to correlate with disease recurrence and metastasis (local and distant). Moreover, in addition to associating with SRC-1, HOXC11 was found to be a strong predictor of reduced disease-free survival on endocrine treatment (Hazard ratio: 5.79; p<0.0001).
 Bioinformatic analysis identified S100β as a target gene of the HOXC11 transcription factor. Interestingly, the s100 family of calcium binding proteins has been associated with poor outcome and reduced disease-free survival in melanoma. Reporter assays were used to confirm HOXC11 as a mediator of S100β transcription. Regulation of the target gene in the presence of tamoxifen was shown to be modified by activation of protein kinase A (PKA) which has previously been implicated in the enhancement of tamoxifenÂs agonist profile. Here we have defined HOXC11 as a non-steroidal interacting partner of SRC-1; furthermore, this interaction appears to be regulated by the activation of PKA. HOXC11 expression in our breast cancer patient cohort associated with poor survival and the development of metastatic disease. This study provides evidence of a novel mechanism at play in endocrine resistant breast cancer cells. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3038.