The p63/p73 network mediates chemosensitivity to cisplatin in a biologically defined subset of primary breast cancers
Chee-Onn Leong, … , Dennis Sgroi, Leif W. Ellisen
Chee-Onn Leong, … , Dennis Sgroi, Leif W. Ellisen
Published May 1, 2007
Citation Information: J Clin Invest. 2007;117(5):1370-1380. https://doi.org/10.1172/JCI30866.
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Research Article Oncology

The p63/p73 network mediates chemosensitivity to cisplatin in a biologically defined subset of primary breast cancers

Abstract

Breast cancers lacking estrogen and progesterone receptor expression and Her2 amplification exhibit distinct gene expression profiles and clinical features, and they comprise the majority of BRCA1-associated tumors. Here we demonstrated that the p53 family member p63 controls a pathway for p73-dependent cisplatin sensitivity specific to these “triple-negative” tumors. In vivo, ΔNp63 and TAp73 isoforms were coexpressed exclusively within a subset of triple-negative primary breast cancers that commonly exhibited mutational inactivation of p53. The ΔNp63α isoform promoted survival of breast cancer cells by binding TAp73 and thereby inhibiting its proapoptotic activity. Consequently, inhibition of p63 by RNA interference led to TAp73-dependent induction of proapoptotic Bcl-2 family members and apoptosis. Breast cancer cells expressing ΔNp63α and TAp73 exhibited cisplatin sensitivity that was uniquely dependent on TAp73. Thus, in response to treatment with cisplatin, but not other chemotherapeutic agents, TAp73 underwent c-Abl–dependent phosphorylation, which promoted dissociation of the ΔNp63α/TAp73 protein complex, TAp73-dependent transcription of proapoptotic Bcl-2 family members, and apoptosis. These findings define p63 as a survival factor in a subset of breast cancers; furthermore, they provide what we believe to be a novel mechanism for cisplatin sensitivity in these triple-negative cancers, and they suggest that such cancers may share the cisplatin sensitivity of BRCA1-associated tumors.

Authors

Chee-Onn Leong, Nick Vidnovic, Maurice Phillip DeYoung, Dennis Sgroi, Leif W. Ellisen

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Figure 2

Endogenous p63 is required for survival in breast cancer cells.

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Endogenous p63 is required for survival in breast cancer cells. (A) Knoc...
(A) Knockdown of endogenous p63–induced Puma, Noxa, and PARP-1 cleavage, as assessed by immunoblot of the indicated cells 72 hours after infection with lentiviral shRNA vectors targeting 2 distinct p63 sequences (p63si-1 and p63si-2) or a nonspecific sequence (si-NS). None of these effects were observed in MCF-7 cells, which do not express abundant p63. (B) Apoptotic morphology following lentiviral p63 knockdown in HCC-1937 cells. Photomicrographs were taken 72 hours after lentiviral shRNA infection. Original magnification, ×100. (C) Apoptosis was observed following endogenous p63 knockdown, as assessed by annexin V/PI staining of unfixed cells 72 hours following infection with the indicated lentiviral shRNA vectors. Percentages indicate apoptotic cells (annexin V–positive and/or PI-positive). (D) Apoptosis following p63 inhibition was specific to breast cancer cells expressing abundant p63. Shown are results of annexin V/PI staining for 3 independent experiments. Error bars represent SD. (E) Puma and Noxa were induced following p63 knockdown. RNA was prepared 72 hours following lentiviral infection and assayed by QRT-PCR for the indicated genes. Error bars represent SD for 2 independent experiments, each performed in duplicate.