Betsy DeVos' nomination to be the next education secretary was in serious trouble Wednesday, after two Senate Republicans said they would vote against her.

Sens. Susan Collins, R-Maine, and Lisa Murkowski, R-Alaska, both said they wouldn't support DeVos.

The two lost GOP votes could put DeVos at risk of being the first of President Trump's nominees not to be confirmed. The defections mean the most she could win is 50 votes from Republicans, and if she gets no support from Democrats, Vice President Mike Pence would have to vote in favor of her to break a 50-50 tie.

Losing another GOP senator would likely doom her nomination. But when asked if the White House had any worries that she won't be confirmed, spokesman Sean Spicer said, "zero."

"I am 100 percent confident she will be the next secretary of education," he said. "I think the games that are being played with Betsy DeVos are sad."

Collins said she was worried that DeVos wouldn't do enough to help public schools, and issue Democrats have also raised during the public debate about Trump's nominee.

"This is not a decision that I have made lightly," Collins said. "I have a great deal of respect for Mrs. DeVos. I believe that she is a good person. I know that she cares deeply about the children of this nation. But for the reasons that I will explain, I simply cannot support her confirmation."

"The mission of the Department of Education is fraught, but supporting public education is at its core," she added. "I'm concerned that Mrs. DeVos' lack of experience with public schools will make it difficult for her to fully understand, identify and assist with those challenges, particularly for our rural schools."

On the Senate floor, Murkowski said she "cannot support this nominee."

In an early procedural vote, however, both Collins and Murkowski supported a motion to proceed to consideration of DeVos' nomination. The next hurdle is expected next week, when the Senate will vote to end debate on the nomination, which needs a simple majority.

While DeVos' nomination is on shaky ground, she got a boost as Sen. Dean Heller, R-Nev., who announced that he will support her nomination. Democrats had hoped that could be the third Republican to break ranks and doom her chances of passing the upper chamber, and were hoping Heller might be an ally.

Gabby Morrongiello contributed