Purpose: Estrogen receptor-a (ER-a) and-h (ER-h) play important roles in the carcinogenesis of breast tumors. Similarly, there have been several reports of ER expression in lung cancers, but the results have not been consistent, and the receptors' prognostic value remains unclear. Our goal was to investigate ER expression in non^small cell lung cancer (NSCLC) and to assess whether their expression correlates with prognosis. Experimental Design: ER expression was examined using immunohistochemical methods with sections from 132 resected NSCLC specimens. Kaplan-Meier survival curves were analyzed to determine the significance of ER expression in the prognosis of NSCLC patients. Results: ER-a was detected in the cytoplasm of 73% of the specimens analyzed, whereas ER-h was detected in the nucleus of 51%. ER-a expression correlated with poorer overall survival (P < 0.001), as did the absence of ER-h expression (P = 0.048). Likewise, at histopathologic stage I, ER-a expression (P = 0.028) or the absence of ER-h (P = 0.

The interaction between 17␤-estradiol and estrogen receptor alpha (ER-␣) plays an important role in breast carcinogenesis and breast cancer treatment. ER-␣ is a critical growth regulatory gene in breast cancer and its expression level is tightly linked to the prognosis and treatment outcomes of breast cancer patients. Loss of ER-␣ expression in breast epithelial cells is critical for breast cancer progression. The underlying molecular mechanisms for this loss, however, are poorly defined. Histone deacetylases (HDACs) are implicated in the alteration of chromatin assembly and tumorigenesis. We show that histone deacetylase 1 (HDAC1) interacts with ER-␣ in vitro and in vivo and suppresses ER-␣ transcription activity. The interaction of HDAC1 with ER-␣ was mediated by the AF-2 and DBD domains of ER-␣. We observed an endogenous interaction of HDAC1 with ER-␣ in breast cancer cells, which was decreased in the presence of estrogen. Interestingly, overexpression of HDAC1 in stable transfected MCF-7 clones induced loss of ER-␣ and significantly increased cell proliferation and colony formation, as compared to the control MCF-7 cells, whereas treatment of stable MCF-7 clones with the HDAC specific inhibitor trichostatin A (TSA) induced re-expression of ER-␣ mRNA and protein. Our findings strongly suggest that HDAC1 affects breast cancer progression by promoting cellular proliferation in association with a reduction in both ER-␣ protein expression and transcriptional activity. Thus, HDAC1 may be a potential target for therapeutic intervention in the treatment of a subset of ER-negative breast cancers.

Lymphatic flux from a primary tumor initially flows into a tumor-draining lymph node (LN), the so-called sentinel LN (SLN). Carried by the lymph fluid are a variety of mediators produced by the tumor that can influence immune responses within the SLN, making it a good model with which to investigate tumor-related immunology. For instance, dendritic cell (DC) numbers are reduced in SLNs from melanoma and breast cancer patients. In the present study, we investigated the mechanism by which DC numbers were reduced within SLNs from patients with non-small cell lung cancer. We found that the incidence of apoptosis among DCs was higher in SLNs than in non-SLNs, as were levels of TGFβ-1. In contrast, levels of TGFβ-1 mRNA did not differ between SLNs and non-SLNs, but were 30 times higher in tumors than in either LN type. In vitro, incubation for 2 days with TGFβ-1 induced apoptosis among both cultured DCs and DCs acutely isolated from normal thoracic LNs, effects that were blocked by the TGFβ-1 inhibitor DAN/Fc chimera. Taken together, these results suggest that tumor-derived TGFβ-1 induces immunosuppression within SLNs before the movement of tumor cells into the SLNs, thereby facilitating metastasis within those nodes.

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