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Estrogen receptor-␣ (ER␣) promotes proliferation of breast cancer cells, whereas tumor suppressor protein p53 impedes proliferation of cells with genomic damage. Whether there is a direct link between these two antagonistic pathways has remained unclear. Here we report that ER␣ binds directly to p53 and represses its function. The activation function-2 (AF-2) domain of ER␣ and the C-terminal regulatory domain of p53 are necessary for the interaction. Knocking down p53 and ER␣ by small interfering RNA elicits opposite effects on p53-target gene expression and cell cycle progression. Remarkably, ionizing radiation that causes genomic damage disrupts the interaction between ER␣ and p53. Ionizing radiation together with ER␣ knock down results in an additive effect on transcription of endogenous p53-target gene p21 (CDKN1) in human breast cancer cells. Our findings reveal a novel mechanism for regulating p53 and suggest that suppressing p53 function is an important component in the proproliferative role of ER␣.As a tumor suppressor, p53 plays a central role in cellular processes such as cell cycle arrest, apoptosis, senescence, and differentiation (1, 2). Although these functions of p53 are essential to prevent cells from becoming cancerous, left uncontrolled, they can lead to consequences deleterious to normal cells. Mutations in the p53 gene or aberrations in the mechanisms to balance p53 function pave the way to tumorigenesis (3). p53 elicits its biological functions mainly by functioning as a transcriptional regulator of various cellular genes with p53-response elements. On the other hand, estrogen receptor-␣ (ER␣) 5 regulates growth and development of various tissues and promotes proliferation of breast cancer cells (4 -8). ER␣ is a transcriptional regulator that is recruited to the promoter regions of target genes directly through binding to estrogen response elements (EREs) or indirectly through other DNA-binding factors, such as AP1 and Sp1 (7, 9). The opposing functions of p53 and ER␣, while stringently controlled in normal cells, are likely disrupted in cancer cells. Various observations have alluded to the potential for a cross-talk between p53 and ER␣ signaling pathways. For example, in murine models, early exposure to 17␤-estradiol (E 2 ) and progesterone to mimic pregnancy induced nuclear p53 enabling resistance to carcinogenesis by blocking proliferation of apparently ER␣-positive cells (10). In breast cancer cells, increased expression of ER␣ led to elevated levels of p53 and MDM2, an inhibitor of p53 function (11), whereas overexpression of MDM2 enhanced the function of ER␣ (12). However, whether there is a direct link between the p53 and ER␣ pathways has remained unclear. To address this important issue, we investigated whether ER␣ directly interacts with p53 and affects its function. EXPERIMENTAL PROCEDURESCell Culture and Irradiation-MCF7 cells and Saos2 cells were maintained in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum (FBS) (Invitrogen) or 10% dextran-charcoal-t...

Biofilm-related infections caused by Candida albicans and associated drug resistant micro-organisms are serious problems for immunocompromised populations. Molecules which can prevent or remove biofilms are needed. Twenty-eight terpenoids of plant origin were analysed for their activity against growth, virulence attributes, and biofilms of C. albicans. Eighteen molecules exhibited minimum inhibitory concentrations of <2 mg ml(-1) for planktonic growth. Selected molecules inhibited yeast to hyphal dimorphism at low concentrations (0.031-0.5 mg ml(-1)), while adhesion to a solid surface was prevented at 0.5-2 mg ml(-1). Treatment with 14 terpenoids resulted in significant (p < 0.05) inhibition of biofilm formation, and of these, linalool, nerol, isopulegol, menthol, carvone, α-thujone, and farnesol exhibited biofilm-specific activity. Eight terpenoids were identified as inhibitors of mature biofilms. This study demonstrated the antibiofilm potential of terpenoids, which need to be further explored as therapeutic strategy against biofilm associated infections of C. albicans.

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