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Mc Adams' break-out role came in 2004, when she starred in the comedy film Mean Girls opposite Lindsay Lohan, Lacey Chabert, and Amanda Seyfried, based on Rosalind Wiseman's book Queen Bees and Wannabes.Mc Adams was 25 years old when she was cast as the mean high school queen bee Regina George, and she modelled her character on Alec Baldwin's performance in the drama Glengarry Glen Ross (1992).Afterwards, Mc Adams starred opposite Cillian Murphy in Wes Craven's psychological thriller Red Eye, where she played a young hotel manager who is held captive by Murphy's character while aboard a red-eye flight.Craven has said Mc Adams was the only actress he considered for the part.
She returned to prominence in 2009, by appearing in the political thriller State of Play, the science-fiction romantic drama The Time Traveler's Wife, and the mystery action-adventure film Sherlock Holmes.
Vanity Fair invited Mc Adams, along with actresses Scarlett Johansson and Keira Knightley, to appear on its March 2006 cover, the annual Hollywood issue.
Upon arrival on the photo set, Mc Adams discovered it was a nude session, declined and left.
She starred with Pierce Brosnan and Chris Cooper in the 1940s film noir Married Life where she played Kay Nesbitt, a young widow who wins the affections of Brosnan and Cooper's older characters.
In preparation for the role, Mc Adams studied old films, particularly those of Kim Novak.