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Simple Summary: Selective estrogen receptor modulators are a major treatment modality for estrogen receptor-positive breast cancers, but the emergence of resistance or a lack of initial responsiveness is a major cause of treatment failures. This study describes TMEM97, also known as sigma 2 receptor, as a novel regulator of estrogen receptor activation. High expression of TMEM97 is found in breast tumor tissues with estrogen receptor positivity. Depletion of TMEM97 expression reduces estrogen receptor activities and breast cancer cell growth. Increased expression of TMEM97 in breast cancer cells stimulates estrogen receptor activities and growth. Further, TMEM97 increases the resistance of breast cancer cells to tamoxifen through elaborating the mTOR/S6K1 signaling. The results suggest an important role for TMEM97 in estrogen receptor activation and resistance to tamoxifen in breast cancer cells. Aberrant estrogen receptor (ER) signaling is a major driver of breast tumor growth and progression. Sigma 2 receptor has long been implicated in breast carcinogenesis based on pharmacological studies, but its molecular identity had been elusive until TMEM97 was identified as the receptor. Herein, we report that the TMEM97/sigma 2 receptor is highly expressed in ER-positive breast tumors and its expression is strongly correlated with ERs and progesterone receptors (PRs) but not with HER2 status. High expression levels of TMEM97 are associated with reduced overall survival of patients. Breast cancer cells with increased expression of TMEM97 had a growth advantage over the control cells under both nutrition-limiting and sufficient conditions, while the knockdown of TMEM97 expression reduced tumor cell proliferations. When compared to their vector control cells, MCF7 and T47D cells with increased TMEM97 expression presented increased resistance to tamoxifen treatment and also grew better under estrogen-depleted conditions. The TMEM97/sigma 2 receptor enhanced the ERα transcriptional activities and increased the expression of genes responsive to estrogen treatment. Increased TMEM97 also stimulated the mTOR/S6K1 signaling pathways in the MCF7 and T47D cells. The increased level of active, phosphorylated ERα, and the enhanced resistance to tamoxifen treatment with increased TMEM97, could be blocked by an mTOR inhibitor. The knockdown of TMEM97 expression reduced the ERα and mTOR/S6K1 signaling activities, rendering the cells with an increased sensitivity to tamoxifen. The observations suggest that the TMEM97/sigma 2 receptor is a novel regulator of ERα activities in breast tumor cell growth. [ABSTRACT FROM AUTHOR]

Research has been conducted on the 12-lipoxygenase (12-LOX) platelet isoform. The isolation of the cDNAs encoding 12-LOX interacting proteins has been carried out.

Abstract Progerin is a truncated form of lamin A. It is identified in patients with Hutchinson-Gilford progeria syndrome (HGPS), a disease characterized by accelerated aging. The contribution of progerin toward aging has been shown to be related to increased DNA damages. Since aging is one major risk factor for carcinogenesis, and genomic instability is a hallmark of malignant cancers, we investigated the expression of progerin in human cancer cells, and whether its expression contributes to carcinogenesis. Using RT-PCR and Western blotting, we detected the expression of progerin in prostate PC-3, DU145 and LNCaP cells at mRNA and protein levels. Ectopic progerin expression did not cause cellular senescence in PC-3 or MCF7 cells. PC-3 cells progerin transfectants were sensitized to DNA damage agent camptothecin (CPT); and persistent DNA damage responses were observed, which might be caused by progerin induced defective DNA damage repair. In addition, progerin transfectants were more tumorigenic in vivo than vector control cells. Our study for the first time describes the expression of progerin in a number of human cancer cell lines and its contributory role in tumorigenesis.

Thromboxane (TX) synthase metabolizes a cyclooxygenase (COX) product, prostanglandin [H.sub.2], into thromboxane [A.sub.2] ([TXA.sub.2]), which is a potent modulator of platelet aggregation. Here we report that human prostate cancer (PCa) cells express TX synthase and that this enzyme is involved in PCa cell motility and tumor growth in vivo. Immunohistochemical analysis of PCa specimens revealed that 58% of cases (n = 24) have moderate or strong expression of TX synthase. In human PCa cell lines, PC-3, PC-3M and ML-2 cells expressed higher levels of TX synthase than did normal prostate epithelial cells or other PCa cell lines such as DU145. [TXA.sub.2] production was reduced by 86% in PC-3 cells when they were treated with carboxyheptal imidazole (CI), an inhibitor of TX synthase, at 10 [+ or -]mol/L. Treatment of PC-3 cells with a COX-1-specific inhibitor, piroxicam, reduced [TXA.sub.2] synthesis by 45-50% whereas the COX-2-specific inhibitor NS398 reduced [TXA.sub.2] production by 75-80%, suggesting that TX synthase activity is dependent on COX-2 and to a lesser extent COX-1 to supply the substrate prostanglandin [H.sub.2]. Inhibition of TX synthase activity with CI significantly reduced PC-3 cell migration on fibronectin in vitro and the growth of tumors derived from PC-3 cells in vivo. Our data suggest that human PCa cells express TX synthase and that this enzyme may modulate PCa growth and progression.

Cellular metabolism of free fatty acids can generate a number of bioactive lipids. 12(S)-Hydroxyeicosatetraenoic acid (HETE), an eicosanoid with potent biological activities including promoting tumor progression, is formed through 12-lipoxygenase (LOX)-mediated arachidonic acid metabolism. Previously, we found that platelet-type 12-LOX is expressed in human prostate cancer and that its level of expression is positively correlated with tumor stage (Gao et at. 1995). When overexpressed in human prostate cancer PC-3 cells, 12-LOX stimulated prostate tumor growth by increasing the angiogenic potential of cancer cells (Nie et al. 1998). Here we present evidence indicating that the expression of vascular endothelial growth factor (VEGF), a putative angiogenic factor, is regulated by 12-LOX and 12(S)-HETE in PC-3 cells. In 12-LOX-transfected PC-3 cells, VEGF production in culture media was increased threefold over that from vector controls. Northern blot analysis found an increase in VEGF mRNA levels in 12-LOX-transfected PC-3 cells. Using VEGF promoter luciferase constructs, we found a 10-fold increase in VEGF promoter activity in 12-LOX-transfected PC-3 cells. Inhibition of 12-LOX activity with nordihydroguaiaretic acid, a general LOX inhibitor, and baicalein, a specific 12-LOX inhibitor, reduced VEGF production in PC-3 cells. Neutralization of VEGF function by a function-blocking antibody significantly decreased the ability of 12-LOX-transfected PC-3 cells to stimulate endothelial cell migration, suggesting that the increased VEGF production in 12-LOX-transfected PC-3 cells accounts, at least partially, for the increased angiogenic potential of 12-LOX-transfected PC-3 cells. We also present data indicating that 12-LOX enhances the metastatic potential of human prostate cancer cells and that a 12-LOX inhibitor, BMD188, reduced the growth of prostate tumors in a severe combined immunodeficient (SCID) mice human bone model. Our data provide insights into the multifaceted effects of arachidonic acid metabolites such as 12(S)-HETE on tumor progression.