Jean M. Gudas

Cyclin E2, a novel G1 cyclin that binds Cdk2 and is aberrantly expressed in human cancers.

ABSTRACT A novel cyclin gene was discovered by searching an expressed sequence tag database with a cyclin box profile. The human cyclin E2 gene encodes a 404-amino-acid protein that is most closely related to cyclin E. Cyclin E2 associates with Cdk2 in a functional kinase complex that is inhibited by both p27Kip1 and p21Cip1. The catalytic activity associated with cyclin E2 complexes is cell cycle regulated and peaks at the G1/S transition. Overexpression of cyclin E2 in mammalian cells accelerates G1, demonstrating that cyclin E2 may be rate limiting for G1 progression. Unlike cyclin E1, which is expressed in most proliferating normal and tumor cells, cyclin E2 levels were low to undetectable in nontransformed cells and increased significantly in tumor-derived cells. The discovery of a novel second cyclin E family member suggests that multiple unique cyclin E-CDK complexes regulate cell cycle progression.

Inhibition of BRCA-1 expression by benzo[a]pyrene and its diol epoxide.

The objective of this study was to investigate whether polycyclic aromatic hydrocarbons (PAHs) contribute to the etiology of sporadic breast cancer by altering the expression of BRCA‐1. Acute exposure to the PAH benzo[a]pyrene (B[a]P) inhibited in a time‐ and dose‐dependent fashion cell proliferation and levels of BRCA‐1 mRNA and protein in estrogen receptor (ER)–positive breast MCF‐7 and ovarian BG‐1 cancer cells. Moreover, the acute exposure to B[a]P abrogated estrogen induction of BRCA‐1 in MCF‐7 cells. The loss of BRCA‐1 expression was prevented by the aromatic hydrocarbon receptor (AhR) antagonist α‐naphthoflavone, suggesting participation of the AhR pathway. BRCA‐1 exon 1a transcripts were downregulated by B[a]P faster than exon 1b mRNA was. Long‐term exposure to B[a]P (40 nM for 15 mo) lowered BRCA‐1 mRNA levels in subclones of MCF‐7 and BG‐1 cells, whereas expression of BRCA‐1 in these clones was reverted to normal levels by washing out of B[a]P. The mechanisms of BRCA‐1 repression by B[a]P were further investigated by examining the effects of the halogenated aryl hydrocarbon 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) and the B[a]P metabolite 7r,8t‐dihydroxy‐9t,10t‐epoxy‐7,8,9,10‐tetrahydrobenzo[a]pyrene (BPDE). While TCDD did not influence basal BRCA‐1 mRNA and protein levels at any of the doses (from 10 nM to 1 μM) tested in this study, treatment with 50 nM BPDE drastically reduced BRCA‐1 mRNA levels, indicating that metabolism of B[a]P to BPDE may contribute to downregulation of BRCA‐1. Conversely, ER‐negative breast MDA‐MB‐231 and HBL‐100 cancer cells were refractory to treatment with B[a]P or TCDD and expressed constant levels of BRCA‐1 mRNA and protein. We conclude that B[a]P may be a risk factor in the etiology of sporadic breast cancer. Mol. Carcinog. 26:100–118, 1999.