P4-01-10: The Role of the Steroid Receptor Coactivator SRC1 and Its Functional Partner HOXC11 in the Development of Endocrine Resistant Breast Cancer.

Background: The steroid receptor coactivator; SRC1, has been well described in the development of endocrine resistant breast cancer. SRC1 associates with clinically aggressive tumours and promotion of distant metastasis. It directly interacts with the developmental transcription factor, HOXC11 and together they are found to strongly predict poor disease-free survival in breast cancer patients (hazard ratios: 5.79; P Materials and Methods: Cells which are resistant to tamoxifen (LY2s) have enhanced SRC1 and HOXC11 mRNA and protein expression in comparison to their endocrine sensitive parent cells (MCF-7s). ChIP-sequencing data for SRC1- and HOXC11- DNA interactions in conjunction with DNA microarray and RNA-sequencing data identified potential signalling targets at play in the LY2 model of endocrine resistance. Real-time analysis and flow cytometry confirmed these interactions at a transcriptional and protein level. These observations were further confirmed in primary breast cancer cultures using flow cytometry. Results: SRC1 and HOXC11 interactions are driven in tamoxifen treated LY2 resistant cells. Combined SRC1 ChIP-sequencing and expression array data analysed in conjunction with HOXC11 ChIP-sequencing and RNA-sequencing data reveal that the SRC1/HOXC11 transcriptional process can orchestrate the loss of luminal cell markers such as ERα, CD24 and PTCH1 whilst concomitantly upregulating mediators of tumourigenicity such as CD44 and MSI2. Primary breast cancer cultures confirm the loss of CD24 in tamoxifen resistant patients. In these patients, loss of CD24 was accompanied by loss of steroid receptor expression (ERα and PR) and by a gain of the basal marker CD44. Discussion: Here, we describe a new signalling pathway where SRC1 and HOXC11 regulate two distinct but complementary mechanisms to drive tumour adaptability. Silencing of luminal cell markers and a concomitant increase in a basal cell phenotype has the potential to alter the survival mechanism of breast cancer cells to evade targeted therapy. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-01-10.