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Cabrillo was born in Castile, Spain. Not much is known about Cabrillo's early years. His nationality was first addressed by a contemporary Spanish chronicler named Antonio.
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In 1502 he joined an expedition to the West Indies. Cabrillo heard the stories about the New World then joined the expedition to the West Indies led by Nicolas de Ovando with Diego Velazquez. The Ovando voyage consisted of 2500 soldiers, settlers in a fleet of 30 ships
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Cabrillo joined Hernando Cortez for his expedition to Mexico. In Mexico Cabrillo helped Cortez defeat the Aztecs. Cabrillo fought as a captain of crossbowmen. He then went through expeditions through Guatemala, and southern Mexico.
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After one of his adventures, he returned to Spain in 1532 then married a woman named Beatriz Sanchez de Ortega. He took an indigenous woman as his common-law wife and had three daughters. Later he married the Spanish Beatriz Sanchez de Ortega in Seville during a visit in Spain.
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In 1533 Cabrillo and Beatriz returned to Guatemala. They had two sons. In Guatemala developed a shipbuilding company and used the ships on the trade routes from the New World back to Spain.
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In 1540 the fleet sailed from El Salvador, and reached Navidad, Mexico, on Christmas Day. While in Mexico, Pedro de Alvarado went to the assistance of the town of Jalisco which was under control by hostile Indians. He was killed when his horse fell on him, crushing his chest. Following Alvarado's death the Viceroy of Mexico took possession of Alvarado's fleet.
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Cabrillo left from Port Navidad on an expedition to explore the western coast of America.
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Cabrillo landed in San Diego Bay and then named it San Miguel. This was an important moment for him because he changed the name of the area.
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He died on San Miguel Island because of a broken leg. The injury developed gangrene and he got infected. A head stone was later found on San Miguel Island.
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Cabrillo's second in command returned to Port Navidad after Cabrillo's death.