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.
View: Text | PDF
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

×

Figure 1

Coexpression of ΔNp63 and TAp73 in triple-negative primary breast tumors.

Options: View larger image (or click on image) Download as PowerPoint
Coexpression of ΔNp63 and TAp73 in triple-negative primary breast tumors...
(A) Overexpression of p63 in primary microdissected invasive breast carcinomas relative to specimen-matched normal luminal epithelia. The ratio of tumor/normal p63 mRNA was determined by QRT-PCR. (B) Nuclear p63 protein correlated with p63 mRNA expression, as assessed by immunohistochemistry of representative tumors from A. Photomicrographs demonstrate low and high expression of p63 mRNA. Original magnification, ×100. (C) TAp73 was overexpressed in ER/PR-negative tumors. Shown is QRT-PCR for TAp73 in 14 ER-positive and 23 ER/PR-negative primary breast carcinomas. Statistical significance was analyzed using both a mean-value approach (ER-positive, 0.373 ± 0.126; ER/PR-negative, 1.381 ± 0.303; P = 0.0172, 2-way Student’s t test) and a binning approach whereby tumors exhibiting p73 expression more than 2-fold the mean of the sample set were categorized as high and the rest as low (P = 0.0309, Fisher’s exact test). (D) Expression of TAp73 correlated with ΔNp63 overexpression (P = 0.0107, Fisher’s exact test) and with p53 mutation (P = 0.0257, Fisher’s exact test) in ER/PR-negative primary breast carcinomas. Levels of ΔNp63 were determined by QRT-PCR, and p53 mutation was determined by cDNA sequencing. Note that TAp73/ΔNp63 coexpression was not observed in Her2-overexpressing tumors as assessed by QRT-PCR.