Chromatin Remodeling Factors and BRM/BRG1 Expression as Prognostic Indicators in Non-Small Cell Lung Cancer

Abstract

We immunohistochemically examined 12 core proteins involved in the chromatin remodeling machinery using a tissue microarray composed of 150 lung adenocarcinoma (AD) and 150 squamous cell carcinoma (SCC) cases. Most of the proteins showed nuclear staining, whereas some also showed cytoplasmic or membranous staining. When the expression patterns of all tested antigens were considered, proteins with nuclear staining clustered into two major groups. Nuclear signals of BRM, Ini-1, retinoblastoma, mSin3A, HDAC1, and HAT1 clustered together, whereas nuclear signals of BRG1, BAF155, HDAC2, BAF170, and RbAP48 formed a second cluster. Additionally, two thirds of the cases on the lung tissue array had follow-up information, and survival analysis was performed for each of the tested proteins. Positive nuclear BRM (N-BRM) staining correlated with a favorable prognosis in SCC and AD patients with a 5 year-survival of 53.5% compared with 32.3% for those whose tumors were negative for N-BRM (P ‫؍‬ 0.015). Furthermore, patients whose tumors stained positive for both N-BRM and nuclear BRG1 had a 5 year-survival of 72% compared with 33.6% (P ‫؍‬ 0.013) for those whose tumors were positive for either or negative for both markers. In contrast, membranous BRM (M-BRM) staining correlated with a poorer prognosis in AD patients with a 5 year-survival of 16.7% compared with those without M-BRM staining (38.1%; P ‫؍‬ 0.016). These results support the notion that BRM and BRG1 participate in two distinct chromosome remodeling complexes that are functionally complementary and that the nuclear presence of BRM, its coexpression with nuclear BRG1, and the altered cellular localization of BRM (M-BRM) are useful markers for nonsmall cell lung cancer prognosis.

SWI/SNF Chromatin Remodeling ATPase Brm Regulates the Differentiation of Early Retinal Stem Cells/Progenitors by Influencing Brn3b Expression and Notch Signaling

“…In both E14 and E18 retina, Brm immunoreactivities were predominantly localized toward the scleral side where differentiating precursors are located. As reported previously, Brm immunoreactivities had nuclear as well as cytoplasmic localization (47). Next, to test whether or not Brm expression is associated with differentiating precursor population, we examined the cellular distribution of Brm immunoreativities in the retina of E14 and E18 embryos, pre-exposed to BrdUrd in utero to identify proliferating (BrdU ϩ ) cells (Fig.…”

The reversible epigenetic silencing of BRM: implications for clinical targeted therapy

“…We and others have observed that BRM expression is lost in lung cancer cell lines as well as in primary lung cancers (Reisman et al, 2003;Fukuoka et al, 2004). The frequency of BRM loss in primary cancers other than lung has not yet been determined, although loss of BRM in a variety of cancer cell lines has been reported (Muchardt and Yaniv, 2001;Reisman et al, 2003).…”

The SWI/SNF complex and cancer

“…Intriguingly, loss of either BRG1 or BRM was observed at a much lower frequency than loss of both ATPases. But both BRG1 and BRM are concomitantly lost in about 15-20% of primary nonsmall-cell lung cancers (Reisman et al, 2003;Fukuoka et al, 2004). Analysis of more than 100 cell lines revealed that both BRG1 and BRM are lost in about 10% of established tumor cell lines .…”

“…The unresolved question is the effect of silencing or mutating the genes that encode both of the catalytic SWI/SNF subunits. Loss of both BRM and BRG1 occurs with significant frequency in many different types of solid tumors, and in lung cancer, loss of both subunits is more common than loss of either, alone (Reisman et al, 2003;Fukuoka et al, 2004). As noted above, BAF47 knockout is the most tumorigenic defect that has been engineered to date.…”