Reactive oxygen species (ROS) constitute a group of highly reactive molecules that have evolved as regulators of important signaling pathways. It is now well accepted that moderate levels of ROS are required for several cellular functions, including gene expression. The production of ROS is elevated in tumor cells as a consequence of increased metabolic rate, gene mutation and relative hypoxia, and excess ROS are quenched by increased antioxidant enzymatic and nonenzymatic pathways in the same cells. Moderate increases of ROS contribute to several pathologic conditions, among which are tumor promotion and progression, as they are involved in different signaling pathways and induce DNA mutation. However, ROS are also able to trigger programmed cell death (PCD). Our review will emphasize the molecular mechanisms useful for the development of therapeutic strategies that are based on modulating ROS levels to treat cancer. Specifically, we will report on the growing data that highlight the role of ROS generated by different metabolic pathways as Trojan horses to eliminate cancer cells.

The molecular mechanisms by which ovarian hormones stimulate growth of breast tumors are unclear. It has been reported previously that estrogens activate the signal‐transducing Src/p21 ras /Erk pathway in human breast cancer cells via an interaction of estrogen receptor (ER) with c‐Src. We now show that progestins stimulate human breast cancer T47D cell proliferation and induce a similar rapid and transient activation of the pathway which, surprisingly, is blocked not only by anti‐progestins but also by anti‐estrogens. In Cos‐7 cells transfected with the B isoform of progesterone receptor (PRB), progestin activation of the MAP kinase pathway depends on co‐transfection of ER. A transcriptionally inactive PRB mutant also activates the signaling pathway, demonstrating that this activity is independent of transcriptional effects. PRB does not interact with c‐Src but associates via the N‐terminal 168 amino acids with ER. This association is required for the signaling pathway activation by progestins. We propose that ER transmits to the Src/p21 ras /Erk pathway signals received from the agonist‐activated PRB. These findings reveal a hitherto unrecognized cross‐talk between ovarian hormones which could be crucial for their growth‐promoting effects on cancer cells.

The p85‐associated phosphatidylinositol (PI) 3‐kinase/Akt pathway mediates the oestradiol‐induced S‐phase entry and cyclin D1 promoter activity in MCF‐7 cells. Experiments with Src, p85α and Akt dominant‐negative forms indicate that in oestradiol‐treated cells these signalling effectors target the cyclin D1 promoter. Oestradiol acutely increases PI3‐kinase and Akt activities in MCF‐7 cells. In NIH 3T3 cells expressing ERα, a dominant‐negative p85 suppresses hormone stimulation of Akt. The Src inhibitor, PP1, prevents hormone stimulation of Akt and PI3‐kinase activities in MCF‐7 cells. In turn, stimulation of Src activity is abolished in ERα‐expressing NIH 3T3 fibroblasts by co‐transfection of the dominant‐negative p85α and in MCF‐7 cells by the PI3‐kinase inhibitor, LY294002. These findings indicate a novel reciprocal cross‐talk between PI3‐kinase and Src. Hormone stimulation of MCF‐7 cells rapidly triggers association of ERα with Src and p85. In vitro these proteins are assembled in a ternary complex with a stronger association than that of the binary complexes composed by the same partners. The ternary complex probably favours hormone activation of Src‐ and PI3‐kinase‐dependent pathways, which converge on cell cycle progression.

Lysine-specific histone demethylase 1 (LSD1) represents the first example of an identified nuclear protein with histone demethylase activity. In particular, it plays a special role in the epigenetic regulation of gene expression, as it removes methyl groups from mono- and dimethylated lysine 4 and/or lysine 9 on histone H3 (H3K4me1/2 and H3K9me1/2), behaving as a repressor or activator of gene expression, respectively. Moreover, it has been recently found to demethylate monomethylated and dimethylated lysine 20 in histone H4 and to contribute to the balance of several other methylated lysine residues in histone H3 (i.e., H3K27, H3K36, and H3K79). Furthermore, in recent years, a plethora of nonhistone proteins have been detected as targets of LSD1 activity, suggesting that this demethylase is a fundamental player in the regulation of multiple pathways triggered in several cellular processes, including cancer progression. In this review, we analyze the molecular mechanism by which LSD1 displays its dual effect on gene expression (related to the specific lysine target), placing final emphasis on the use of pharmacological inhibitors of its activity in future clinical studies to fight cancer.

The recent findings that oestradiol and progestins activate the Src/Ras/Erks signalling pathway raise the question of the role of this stimulation. Microinjection experiments of human mammary cancer‐derived cells (MCF‐7 and T47D) with cDNA of catalytically inactive Src or anti‐Ras antibody prove that Src and Ras are required for oestradiol and progestin‐dependent progression of cells through the cell cycle. The antitumoral ansamycin antibiotic, geldanamycin, disrupts the steroid‐induced Ras–Raf‐1 association and prevents Raf‐1 activation and steroid‐induced DNA synthesis. Furthermore, the selective MEK 1 inhibitor, PD 98059, inhibits oestradiol and progestin stimulation of Erk‐2 and the steroid‐dependent S‐phase entry. The MDA‐MB231 cells, which do not express oestradiol receptor, fail to respond to oestradiol in terms of Erk‐2 activation and S‐phase entry. Fibroblasts are made equally oestradiol‐responsive in terms of DNA synthesis by transient transfection with either the wild‐type or the transcriptionally inactive mutant oestradiol receptor (HE241G). Co‐transfection of catalytically inactive Src as well as treatment with PD98059 inhibit the oestradiol‐dependent S‐phase entry of fibroblasts expressing either the wild‐type oestrogen receptor or its transcriptionally inactive mutant. The data presented support the view that non‐transcriptional action of the two steroids plays a major role in cell cycle progression.

Breast cancer (BC) is a hormone-related tumor. Despite the progress in BC therapy, this disease still remains the most common cancer amongst women around the world. This is likely due to the amazing BC heterogeneity. Accumulating evidence suggests a role for androgen signaling in BC. Nevertheless, a precise understanding of the mechanism of androgen action in this disease remains a challenging puzzle. Androgen receptor (AR) is often expressed in BC and several studies suggest that its role depends on the tumor microenvironment as well as the relative levels of circulating estrogens and androgens. However, the AR function in BC is still conflicting. Although AR expression is often associated with a favorable prognosis in EREstradiol Receptorα-positive (ERα +) BC, many findings suggest that, in some instances, high levels of AR can contribute to the therapy-resistance. Again, in ERα negative BC (ERα –), AR is mainly expressed in tumors with apocrine differentiation and a lower Nottingham grade. Moreover, AR stimulates cellular proliferation in triple negative breast cancer (ERα –, PgR –, and HER-2-Neu –). This finding is substantiated by the observation that high levels of circulating androgens are associated with an increased risk of developing BC in post-menopausal woman. Treatment of ERα- BC with AR antagonists, such as bicalutamide or enzalutamide, reduces, indeed, the tumor growth. In this review, we will analyze the putative role of AR in BC. Emerging therapies based on the use of new agonists or antagonists or inhibitors will be here discussed.