Sens. Susan Collins Susan Margaret CollinsGOP short of votes on Trump's controversial Fed pick Congress must save the Postal Service from collapse — our economy depends on it Garcetti: I would have acted sooner if Trump hadn't downplayed virus MORE (Maine) and Lisa Murkowski Lisa Ann MurkowskiGOP ramps up attacks on Democrats over talk of nixing filibuster OVERNIGHT ENERGY: House Democrats tee up vote on climate-focused energy bill next week | EPA reappoints controversial leader to air quality advisory committee | Coronavirus creates delay in Pentagon research for alternative to 'forever chemicals' House Democrats tee up vote on climate-focused energy bill next week MORE (Alaska) in dramatic back-to-back speeches Wednesday said they would oppose confirming Betsy DeVos as Education secretary.

The two became the first Republican senators to break with any of President Trump’s Cabinet picks.

The defections set up a potential 51-50 vote in the Senate to confirm DeVos, with Vice President Pence breaking the tie.

It would be the first time a vice president has been the deciding vote on a nomination, and the first time a vice president has had to break a Senate tie since March 2008, when Vice President Dick Cheney cast a deciding vote on a package of tax cuts.

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DeVos’s nomination will move before Sen. Jeff Sessions Jefferson (Jeff) Beauregard SessionsTrump's policies on refugees are as simple as ABCs Ocasio-Cortez, Velázquez call for convention to decide Puerto Rico status White House officials voted by show of hands on 2018 family separations: report MORE’s nod as attorney general to ensure that the Alabama Republican can cast a vote for Trump’s Education pick.

The Senate could take a final vote on DeVos as soon as Friday, though Democrats are expected to use the Senate’s procedural roadblocks to drag the fight over DeVos into the weekend or early next week.

Republicans expressed confidence that there will be no more defections. They can’t afford any, as no Democrats are set to back DeVos.

“I expect her to be confirmed,” Sen. John Cornyn John Cornyn'Top Chef' star Tom Colicchio presses Congress to boost SNAP benefits during pandemic NJ governor designates Juneteenth as state holiday The Hill's Morning Report - Sponsored by National Industries for the Blind - Prudent or 'pathetic'? GOP senators plan to vote on coronavirus relief Thursday MORE (R-Texas) told reporters. “You can take that to the bank.”

The White House also said it has “zero” concern over DeVos’s nomination being in jeopardy.

“I have 100 percent confidence she will be the next secretary of Education,” White House press secretary Sean Spicer said at his daily briefing with reporters.

He added, “The games being played with Betsy DeVos are sad.”

DeVos, a GOP mega-donor long active on education issues, has been the subject of fierce opposition from teachers unions and other liberal groups opposed to her support for charter schools and tuition vouchers using public funds. Senators in both parties have also criticized her lack of experience with public and rural education.

Liberals made DeVos a top target and sought to jam Republican phone lines with protests over her nomination. Credo Action’s vice president and political director, Murshed Zaheed, told The Hill that its members made 18,000 calls to members of the Senate Health, Education, Labor and Pensions Committee, including specifically targeting Collins, Murkowski and Sen. Rand Paul Randal (Rand) Howard PaulGOP senator to quarantine after coronavirus exposure The Hill's Morning Report - Sponsored by National Industries for the Blind - Trump seeks to flip 'Rage' narrative; Dems block COVID-19 bill Overnight Health Care: Senate Democrats block GOP relief bill | Democrats reveal Medicaid chief's spending on high-paid consultants | Trump calls question about why he 'lied' about COVID-19 a 'disgrace' MORE (R-Ky.).

Murkowski noted that her office had been flooded with calls urging her to oppose DeVos.

“I have heard from thousands, truly thousands, of Alaskans who shared their concerns,” she said from the Senate floor.

Both Collins and Murkowski stressed that they did not make their decision lightly and vouched for DeVos’s personal character, but stressed they ultimately could not support her.

“I come to the floor to announce a very difficult decision that I have made, and that is to vote against the confirmation of Betsy DeVos to be our nation’s next secretary of Education,” Collins said.

Murkowski followed Collins to the floor, stating, “I have serious concerns about a nominee to be secretary of Education ... who has been so immersed in the discussion of vouchers.”

Progressive groups quickly claimed momentum in the fight.

“Betsy DeVos is an enemy of public schools who would let corporations control our children’s education: that’s why there’s a growing bipartisan opposition to her confirmation,” American Bridge, a liberal super PAC, said in a statement.

Every Voice President David Donnelly and End Citizens United Executive Director Tiffany Muller added in a joint statement that Murkowski and Collins’s opposition was a “victory for the grassroots power of the American people.”

DeVos’s troubles come as tensions boil over the pace of confirmations.

Republicans on the Senate Finance Committee on Wednesday changed the rules requiring at least one member of each party to be present so that they could advance Steven Mnuchin to head the Treasury Department and Rep. Tom Price (R-Ga.) as secretary of Health and Human Services.

The Senate managed to confirm Rex Tillerson to be Trump’s secretary of State, but only after Democrats used the Senate’s procedural hurdle to drag out debate over his nomination for days.

Senate Majority Leader Mitch McConnell Addison (Mitch) Mitchell McConnellGOP ramps up attacks on Democrats over talk of nixing filibuster MLB owner: It's 'very necessary' to vote for Trump Delta: Early departures saved flight attendants' jobs MORE (R-Ky.) blasted Democrats over their tactics this week, telling reporters, “It is time to get over the fact that they lost the election.”

DeVos came under fire from Democrats this week over a Washington Post report that several lines and phrases in her committee-submitted questionnaire appeared to be lifted without attribution from other sources, including a news release from a Justice Department official during the Obama administration.

She also endured a rocky confirmation hearing in which she at one point appeared to advocate for guns in school because of the possibility of a grizzly bear attack, at least in Wyoming.

Collins pointed specifically to DeVos’s lack of knowledge about the Individuals with Disabilities Education Act in explaining her decision.

“While it is unrealistic and unfair to expect a nominee to know the details of all the programs under the jurisdiction of the Department of Education, I am troubled and surprised by Mrs. ­DeVos’ apparent lack of familiarity with the landmark 1975 law, the Individuals with Disabilities Education Act, known as IDEA,” she said.

DeVos came under fire on the law during her hearing, when she faced sharp questions from Sen. Maggie Hassan, whose son is disabled.

When DeVos told the New Hampshire Democrat that she was “sensitive to the needs of special needs students,” Hassan fired back: “With all due respect, it’s not about sensitivity, although that helps.”

Sen. Joe Manchin Joseph (Joe) ManchinOVERNIGHT ENERGY: House Democrats tee up vote on climate-focused energy bill next week | EPA reappoints controversial leader to air quality advisory committee | Coronavirus creates delay in Pentagon research for alternative to 'forever chemicals' Senate Democrats demand White House fire controversial head of public lands agency House Democrats tee up vote on climate-focused energy bill next week MORE (D-W.Va.), a vulnerable red-state Democrat up for reelection in 2018, announced he would not support DeVos on Wednesday, saying her “lack of exposure to public education is very concerning for me.”

Another GOP defection appears unlikely, however, as Sen. Dean Heller Dean Arthur HellerOn The Trail: Democrats plan to hammer Trump on Social Security, Medicare Lobbying World Democrats spend big to put Senate in play MORE (R-Nev.), a top Democratic target in 2018, announced he would vote to confirm her.

“Due to her commitment to improve our nation’s school system for all students and her focus on increasing parental engagement, I am supporting Betsy DeVos as our nation’s next Secretary of Education,” Heller said in a statement.

Updated at 8:18 p.m.