Garrett Gomez guided Life Is Sweet from last to first on the far outside of the home straight at Santa Anita.
The 4-year-old filly shares the barn of defending champion Zenyatta, who skipped the race to run in Saturday's $5 million Classic for the first time against the boys. She will put her 13-0 winning streak on the line in the 1 1/4-mile (2,000-meter) race, the richest in North America.
Both horses are trained by John Shirreffs for different owners.
Life Is Sweet ran 1 1-8 miles (1,800 meters) in 1:48.58 and paid $18.20, $8 and $5 at 8-1 odds. She was the fourth longshot to win in the six Breeders' Cup races.
Mushka returned $12.80 and $6.40, while Music Note was another length back in third and paid $3.20 to show. Careless Jewel, the 9-5 wagering favorite, romped to the early lead before fading to last in the field of eight.
American horses won four of the day's six races, with jockey Julien Leparoux riding two winners.
It was the second consecutive Breeders' Cup to be run on Santa Anita's synthetic surface, which kept stellar filly Rachel Alexandra away. She won all of her eight races this year, including three wins over male horses, one of them in the Preakness Stakes. But her owner Jess Jackson doesn't like synthetics, so he shut down the U.S. Horse of the Year favorite.
Man of Iron opened the card with a thrilling nose victory over 9-year-old gelding Cloudy's Knight in the $500,000 Marathon, the day's only race featuring males.
Man of Iron covered 1 3/4 miles (2,800 meters) in 2:54.11 under John Murtagh, giving Irish trainer Aidan O'Brien his fourth career Breeders' Cup victory. The 3-year-old paid $14.80 to win in his U.S. debut after running exclusively in Europe.
Rosemary Homeister Jr. barely missed becoming the second woman to ride a Breeders' Cup winner, losing the photo finish by a bob of her gelding's head.
Midday gave Europe its other victory, winning the $2 million Filly & Mare Turf by a length and snapping a six-race winless streak in the Breeders' Cup by veteran European trainer Henry Cecil.
Ridden by Thomas Queally, Midday ran 1 1/4 miles (2,000 meters) in 1:59.14 and paid $6.60 to win.
She Be Wild charged along the rail to win the $2 million Juvenile Fillies by three-quarters of a length under Leparoux. She ran 1 1-16 miles (1,700 meters) in 1:43.80 and paid $16.80 to win, and improved to four wins in five races on synthetic surfaces.
It was trainer Wayne Catalano's second career Breeders' Cup victory.
The $1 million Juvenile Fillies Turf was won by Tapitsfly, who held off Rose Catherine by a half-length. With Robby Albarado aboard, Tapitsfly ran one mile (1,600 meters) in 1:34.25 and paid $21.60 to win.
Informed Decision won the $1 million Filly & Mare Sprint by 1 1/4 lengths over defending champion Ventura, giving Leparoux his second win of the day. The 4-year-old gray filly covered 7 furlongs in 1:21.66 and paid $8.80 to win.
Trainer Jonathan Sheppard scored his first Breeders' Cup victory on the day, to go with a second by Cloudy's Knight and a third by Forever Together in the Filly & Mare Turf.
Ventura was sent off as the 4-5 wagering favorite. She is trained by Hall of Famer Bobby Frankel, who has run his stable by phone most of the year as he battles an undisclosed illness. His other horses, Proviso in the Ladies' Classic and Visit in the Filly & Mare Turf, both finished fourth.
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