Par-4 Down-regulation Promotes Breast Cancer Recurrence by Preventing Multinucleation following Targeted Therapy
Most deaths from breast cancer result from tumor recurrence, but the mechanisms underlying tumor relapse are largely unknown. We now report that Par-4 is down-regulated during tumor recurrence and that Par-4 down-regulation is necessary and sufficient to promote recurrence. Tumor cells with low Par-...
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| Published in | Cancer cell Vol. 24; no. 1 |
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| Main Authors | , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
13.06.2013
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| Online Access | Get full text |
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| Abstract | Most deaths from breast cancer result from tumor recurrence, but the mechanisms underlying tumor relapse are largely unknown. We now report that Par-4 is down-regulated during tumor recurrence and that Par-4 down-regulation is necessary and sufficient to promote recurrence. Tumor cells with low Par-4 expression survive therapy by evading a program of Par-4-dependent multinucleation and apoptosis that is otherwise engaged following treatment. Low Par-4 expression is associated with poor response to neoadjuvant chemotherapy and an increased risk of relapse in breast cancer patients, and Par-4 is down-regulated in residual tumor cells that survive neoadjuvant chemotherapy. Our findings identify Par-4-induced multinucleation as a mechanism of cell death in oncogene-addicted cells and establish Par-4 as a negative regulator of breast cancer recurrence. |
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| AbstractList | Most deaths from breast cancer result from tumor recurrence, but the mechanisms underlying tumor relapse are largely unknown. We now report that Par-4 is down-regulated during tumor recurrence and that Par-4 down-regulation is necessary and sufficient to promote recurrence. Tumor cells with low Par-4 expression survive therapy by evading a program of Par-4-dependent multinucleation and apoptosis that is otherwise engaged following treatment. Low Par-4 expression is associated with poor response to neoadjuvant chemotherapy and an increased risk of relapse in breast cancer patients, and Par-4 is down-regulated in residual tumor cells that survive neoadjuvant chemotherapy. Our findings identify Par-4-induced multinucleation as a mechanism of cell death in oncogene-addicted cells and establish Par-4 as a negative regulator of breast cancer recurrence. |
| Author | Feng, Yi Alvarez, James V. DeMichele, Angela Pan, Tien-chi Wandless, Thomas J. Chodosh, Lewis A. Ruth, Jason Pant, Dhruv Grimley, Joshua S. Zhou, Alice |
| AuthorAffiliation | 3 Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104 4 Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104 6 University of California San Francisco, 1600 Divisadero Street, Box 1710, San Francisco, CA 94115 2 Department of Cell & Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104 1 Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104 5 Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305 |
| AuthorAffiliation_xml | – name: 2 Department of Cell & Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104 – name: 4 Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104 – name: 6 University of California San Francisco, 1600 Divisadero Street, Box 1710, San Francisco, CA 94115 – name: 3 Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104 – name: 5 Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305 – name: 1 Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104 |
| Author_xml | – sequence: 1 givenname: James V. surname: Alvarez fullname: Alvarez, James V. organization: Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104 Department of Cell & Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104 Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104 Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104 Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305 University of California San Francisco, 1600 Divisadero Street, Box 1710, San Francisco, CA 94115 – sequence: 2 givenname: Tien-chi surname: Pan fullname: Pan, Tien-chi organization: Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104 Department of Cell & Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104 Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104 Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104 Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305 University of California San Francisco, 1600 Divisadero Street, Box 1710, San Francisco, CA 94115 – sequence: 3 givenname: Jason surname: Ruth fullname: Ruth, Jason organization: Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104 Department of Cell & Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104 Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104 Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104 Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305 University of California San Francisco, 1600 Divisadero Street, Box 1710, San Francisco, CA 94115 – sequence: 4 givenname: Yi surname: Feng fullname: Feng, Yi organization: Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104 Department of Cell & Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104 Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104 Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104 Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305 University of California San Francisco, 1600 Divisadero Street, Box 1710, San Francisco, CA 94115 – sequence: 5 givenname: Alice surname: Zhou fullname: Zhou, Alice organization: Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104 Department of Cell & Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104 Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104 Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104 Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305 University of California San Francisco, 1600 Divisadero Street, Box 1710, San Francisco, CA 94115 – sequence: 6 givenname: Dhruv surname: Pant fullname: Pant, Dhruv organization: Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104 Department of Cell & Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104 Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104 Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104 Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305 University of California San Francisco, 1600 Divisadero Street, Box 1710, San Francisco, CA 94115 – sequence: 7 givenname: Joshua S. surname: Grimley fullname: Grimley, Joshua S. organization: Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104 Department of Cell & Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104 Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104 Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104 Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305 University of California San Francisco, 1600 Divisadero Street, Box 1710, San Francisco, CA 94115 – sequence: 8 givenname: Thomas J. surname: Wandless fullname: Wandless, Thomas J. organization: Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104 Department of Cell & Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104 Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104 Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104 Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305 University of California San Francisco, 1600 Divisadero Street, Box 1710, San Francisco, CA 94115 – sequence: 9 givenname: Angela surname: DeMichele fullname: DeMichele, Angela organization: Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104 Department of Cell & Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104 Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104 Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104 Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305 University of California San Francisco, 1600 Divisadero Street, Box 1710, San Francisco, CA 94115 – sequence: 10 organization: Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104 Department of Cell & Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104 Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104 Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104 Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305 University of California San Francisco, 1600 Divisadero Street, Box 1710, San Francisco, CA 94115 – sequence: 11 givenname: Lewis A. surname: Chodosh fullname: Chodosh, Lewis A. organization: Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104 Department of Cell & Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104 Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104 Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104 Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305 University of California San Francisco, 1600 Divisadero Street, Box 1710, San Francisco, CA 94115 |
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| Snippet | Most deaths from breast cancer result from tumor recurrence, but the mechanisms underlying tumor relapse are largely unknown. We now report that Par-4 is... |
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| Title | Par-4 Down-regulation Promotes Breast Cancer Recurrence by Preventing Multinucleation following Targeted Therapy |
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