SRC-1 Promotes Breast Cancer Metastasis by Activating MAPK Pathway.

Abstract

Abstract Background: Steroid receptor coactivator (SRC-1) was defined as a nuclear receptor coactivator. It interacts with nuclear receptor and other transcriptional factors and promotes target genes expression. In breast cancer, SRC-1 expression correlates positively with HER2 expression, disease recurrence and resistance to endocrine therapy. Our previous work demonstrated that knockout of SRC-1 in mice suppressed breast cancer metastasis without affecting primary tumor initiation and growth in the MMTV-PyMT transgenic mice. However, the molecular mechanism responsible for SRC-1 in breast cancer metastasis is still unclear.Material and Methods: To further study the function of SRC-1 in breast cancer metastasis, we generated transgenic mice with overexpression of human SRC-1 in the mouse mammary epithelial cells. The mammary glands of these mice exhibited normal development. After crossing these mice with MMTV-TVA (avian subgroup A receptor gene, TVA) transgenic mice, we obtained MMTV-TVA/MMTV-hSRC-1 (tester) and MMTV-TVA/WT (control) biogenic mice. RCAS (avian leukosis virus) viruses, which contain MMTV-PyMT expression cassette and can bind to TVA, were injected into mammary gland to induce mammary tumor. Tumor initiation, growth and metastasis were carefully examined with these mice. To investigate mechanism, multiple PyMT tumor cell lines were generated form individual primary tumor with or without SRC-1 and cell migration and invasion were compared with those cells and human breast cancer cells.Results and discuss: No difference in tumor initiation and growth was observed in those mice, but metastasis incidence of breast cancer to lung increased significantly in PyMT/TVA/hSRC-1 mice compared with PyMT/TVA/WT control mice. Tumor metastasis in lung also presented higher index in PyMT/TVA/hSRC-1 mice. In vitro study with PyMT/SRC-1 WT and KO cell lines showed SRC-1 deficiency disturbed cells migration and invasion. WT tumor cells adhered faster to extracellular matrix fibronecetin (FN) and presented high levels of phosphorylated forms of FAK, c-Src, Erk, Jnk and activated Rac1. Western blotting and real-time RT-PCR revealed lower integrin alpha5 and Gem, one of GTP binding protein, levels in SRC-1 deficient tumor cells. In human breast cancer MDA-MB-231 cells, SRC-1 knockdown led to decreased cell migration and invasion. Therefore, SRC-1 may regulate integrin expression and MAPK pathway to promote cancer cell migration and metastasis. Our study provides a possibility to inhibit breast cancer metastasis by targeting SRC-1 function. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6150.