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Progesterone is a sex hormone exerting many effects throughout the body and inhibits cell proliferation in endometrial carcinoma and meningioma. In this study, we examined the status of progesterone receptor (PR) in 228 human lung cancers, and correlated the findings with various clinicopathological parameters. We also examined effects on cell proliferation by progesterone in vivo and in vitro. PR immunoreactivity was inversely associated with Tumour-node-metastasis (TNM) stage, T factor, lymph node metastasis, histological type, or histological differentiation and Ki-67 LI, and was associated with clinical outcome in 228 patients with lung cancer (P < 0.0001), clinical outcome in stage I lung cancer patients (P = 0.0008), and in stage II+III lung cancer patients (P = 0.0027), and PR was found to be an independent prognostic variable in multivariate analysis (P = 0.0003). Inhibition of NSCLC cell growth by progesterone was examined using PR-positive (A549, LCSC#2, and 1-87), or -negative (RERF-LC-OK) NSCLC cell lines. Cell proliferation was inhibited in a dose dependent manner by progesterone in PR-positive NSCLC cell lines and its effects were reversed by PR blocker. Proliferation of these tumor cells transplanted into nude mice was dose-dependently inhibited by progesterone, associated with increment of p21 and p27 and decrement of cyclin A, cyclin E, and Ki67. In addition, progesterone inhibited the cell proliferation in lung cancer cell lines in vitro as well as in vivo via PR. We then examined in situ production of progesterone in lung cancer cell lines and tissue concentrations of progesterone in 30 lung cancer. Cholesterol is known to be transported into mitochondria via steroidogenic acute regulatory protein (StAR). The conversion of cholesterol to pregnenolone via P450 side-chain cleavage (P450scc) and that of pregnenolone to progesterone via 3β-hydroxysteroid dehydrogenase (3β-HSD) are likely to be one mechanism of progesterone synthesis. Progesterone concentrations were significantly higher in adenocarcinoma than in squamous cell carcinoma in lung cancer (p=0.0237), and positively correlated with that of StAR immunoreactivity (p= 0.0004), P450scc (p= 0.0002), and 3βHSD (p=0.0004). Progesterone was produced from LDL in A549 and concentrations of progesterone produced by A549 were significantly higher than those by RERF-LC-OK after 8 and 24 hours (p=0.0002) Results from our present study suggest that both systemically circulated and locally produced progesterone inhibit the growth of lung cancer via PR, and that progesterone or progesterone associated agents can be effective for treatment of inoperable advanced lung cancer patients or recurrence cases following surgery.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]