The SWI/SNF complex is altered in primary tumors and cancer cell lines

Proc Amer Assoc Cancer Res, Volume 46, 2005 2855 The SWI/SNF complex is a key regulator of gene expression and is involved in a number of important signaling pathways. This multimeric chromatin remodeling complex controls gene expression by shifting the position of histones, thereby modifying access of key cellular proteins to specific DNA domains. The function of this complex can be abrogated by the loss of specific subunits and has been implicated in the development of certain human tumors. The BAF47 protein was the first SWI/SNF subunit recognized as a bona fide tumor suppressor protein. The loss of this subunit is known to cause the development of pediatric rhabdoid tumors, and in mice, its heterozygous loss leads to tumor formation. The ATPase subunit BRG1 and its homolog, BRM, are mutually exclusive catalytic subunits which when lost will inactivate the SWI/SNF complex thereby facilitating tumor development. To this end, we have found that heterozygous loss of BRG1 increases the occurrence of lung adenomas four fold in mice exposed to either urethane or the tobacco carcinogen, NNK. This is not surprising since a number of key cellular proteins including Rb, p53 and BRCA1 require a functionally intact SWI/SNF complex. In our previous work, we found that BRG1 and BRM are concomitantly lost in 30-40% of lung cancer cell lines and 10-20% of primary lung cancers. To determine if the SWI/SNF complex was altered in tumors arising from the upper respiratory tract, we investigated the expression of the SWI/SNF units in head/neck cell lines. We found by western blot analysis that BRG1, BRM, BAF57 and/or BAF250 are lost in 12/15 (∼80%) of head/neck cell lines. In those cell lines which have specifically lost BRM and/or BAF57 expression, we also found they lacked CD44 expression and are sensitive to exposure to micromolar concentrations of Cisplatin. By immunostaining, we have also found that BRG1 and BRM expression is absent in 10-20% of primary head/neck tumors. To identify additional tumor types which may harbor alterations in the SWI/SNF complex, we examined the expression of BRG1 and BRM by immunostaining a variety of tissue microarrays. We found that, in addition to lung and head/neck cancers, 5-15% of prostate, bladder, esophageal and ovarian cancers also lose BRG1 and/or BRM expression. This data suggests that loss of SWI/SNF function can occur in a variety of solid tumors and may be a contributing factor in the development of these tumors.