The Role of Ldb1 in ErbB2/Neu-induced Mammary Tumorigenesis

Abstract

The ste-20 like kinase (SLK) is a serine/threonine kinase activated downstream of Neu signaling and functions to mediate efficient migration and invasion of breast cancer cells. Previously, the LIM domain binding protein 1 (Ldb1) has been identified as a negative regulator of SLK kinase activity in MEF3T3 fibroblasts. Ldb1 is a transcriptional cofactor required for normal mouse embryonic development. In the current study we sought to assess the effect of mammary gland-specific Ldb1 deletion on SLK activity and metastasis in a Neu-overexpressing breast cancer model, the MMTV-NIC mouse model. Our results show that Ldb1 deletion does not affect SLK activity in Neu- induced tumors as demonstrated by in-vitro kinase assays. Also, Ldb1 deletion in the mammary epithelium of the MMTV-NIC model does not affect Neu-mediated tumor growth or overall survival. Due to the low incidence of spontaneous metastasis in the model, we performed tail-vein lung colonization assays and found that Ldb1 deletion significantly inhibits the lung colonization capability of primary tumor cells. Taken together, our findings highlight the important implications of understanding Ldb1- mediated transcriptional activity in Neu-overexpressing breast tumors as it could offer therapeutic opportunity to limit the spread of metastatic Neu-induced breast cancers.