MDM2, MDM2-C, and mutant p53 expression influence breast cancer survival in a multiethnic population

Abstract

Purpose: To examine the association between expression of mutant p53 (mtp53), full length MDM2 (MDM2), and MDM2 isoform C (MDM2-C) and survival in multiethnic breast cancer patients. Method: A total of 787 invasive breast tumors included in a clinically-annotated multiethnic population-based tissue microarray (TMA) were screened utilizing commercially available antibodies to p53 and MDM2, and a newly developed monoclonal antibody recognizing MDM2-C. Results: Mutant p53 (mtp53) was more common in younger (<50 yrs) breast cancer patients. Among the 787 cases included in the study, mtp53, MDM2, and MDM2-C expression was not significantly associated with risk of overall or breast cancer-specific mortality. However when associations within individual racial/ethnic groups (White, Japanese, and Native Hawaiian) were examined, expression of MDM2-C was found to be associated with lower risk of breast cancerspecific mortality exclusively for White patients (HR=0.32, 95% CI: 0.15-0.69) and mtp53 expression was associated with higher overall mortality in Japanese patients (HR=1.63, 95% CI: 1.02-2.59). Also, Japanese patients positive for the joint expression of MDM2-C and mtp53 had a greater than 2-fold risk of overall mortality (HR=2.15, 95% CI 1.04-4.48); and White patients with positive MDM2-C and wild-type p53 expression (HR=0.28, 95% CI 0.08-0.96) were at lower risk of mortality when compared to patients negative for MDM2-C and wild-type p53 expression in their respective racial/ethnic group.

The molecular landscape of Asian breast cancers reveals clinically relevant population-specific differences

“…Regardless of the cause of the mutations, TP53 mutations have been suggested to be prognostic, but with opposite effects in different subtypes of breast cancer 52,53 , and in ER+ /HER2− disease, TP53 mutations appear to be associated with higher risk to recurrence and poorer prognosis [54][55][56] . Notably, expression of TP53 mutations may have different effects in different populations 57 , highlighting the need for further clinical studies in diverse populations.…”

<p>MDM2-C Functions as an E3 Ubiquitin Ligase</p>

“…17,18 MDM2-C is highly expressed in breast cancers and maintains a large amount of the original MDM2 structure, keeping a portion of the N-terminal p53 interaction domain, the central acidic domain and zinc finger domains, and the C-terminal RING domain. 19,20 The MDM2-A and MDM2-B isoforms contain E3 ligase activity but the potential for the MDM2-C isoform to regulate ubiquitination pathways has not been explored. 21 The regulation of MDM2 auto-ubiquitination is a central hub for regulating other pathways.…”

“…6,25 MDM2-C transcript and protein are present in liposarcoma and breast cancer tissue and cell-lines and MDM2-C is known to promote tumorigenesis in cells that do not express wildtype p53. 19,20 This suggests that MDM2-C might function as an E3 ubiquitin ligase for itself and other proteins and the resulting ubiquitination patterns that might promote cancer in the presence of mtp53. The ubiquitination of proteins does not always signal for increased protein degradation it can also be a post-translational modification that can alter cellular signaling.…”

The Molecular Landscape of Asian Breast Cancers Reveals Clinically Relevant Population-Specific Differences

“…Regardless of the cause of the mutations, TP53 mutations have been suggested to be prognostic, but with opposite effects in different subtypes of breast cancer 45,46 , and in ER+/HER2-disease, TP53 mutations appear to be associated with higher risk to recurrence and poorer prognosis 47–49 . Notably, expression of TP53 mutations may have different effects in different populations 50 , highlighting the need for further clinical studies in diverse populations.…”