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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Role of p53 in breast cancer progression: An insight into p53 targeted therapy
Charlie Marvalim1, Arpita Datta1, Soo Chin Lee1,2
1Cancer Science Institute of Singapore, Singapore 117599, Singapore.
Abstract:
The transcription factor p53 is an important regulator of a multitude of cellular processes. In the presence of genotoxic stress, p53 is activated to facilitate DNA repair, cell cycle arrest, and apoptosis. In breast cancer, the tumor suppressive activities of p53 are frequently inactivated by either the overexpression of its negative regulator MDM2, or mutation which is present in 30-35% of all breast cancer cases. Notably, the frequency of p53 mutation is highly subtype dependent in breast cancers, with majority of hormone receptor-positive or luminal subtypes retaining the wild-type p53 status while hormone receptor-negative patients predominantly carry p53 mutations with gain-of-function oncogenic activities that contribute to poorer prognosis. Thus, a two-pronged strategy of targeting wild-type and mutant p53 in different subtypes of breast cancer can have clinical relevance. The development of p53-based therapies has rapidly progressed in recent years, and include unique small molecule chemical inhibitors, stapled peptides, PROTACs, as well as several genetic-based approaches using vectors and engineered antibodies. In this review, we highlight the therapeutic strategies that are in pre-clinical and clinical development to overcome p53 inactivation in both wild-type and mutant p53-bearing breast tumors, and discuss their efficacies and limitations in pre-clinical and clinical settings.
Insights
Targeting both wild-type and mutant p53 is crucial for breast cancer therapy. This review explores emerging p53-based treatments, including small molecules and genetic approaches, for diverse breast tumor subtypes.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- The p53 transcription factor is a key tumor suppressor, regulating DNA repair, cell cycle arrest, and apoptosis.
- In breast cancer, p53 function is often lost through MDM2 overexpression or mutation, occurring in 30-35% of cases.
- p53 mutations are subtype-specific, impacting treatment strategies and patient prognosis.
Purpose of the Study:
- To review current pre-clinical and clinical therapeutic strategies targeting p53 inactivation in breast cancer.
- To discuss the efficacy and limitations of p53-based therapies for both wild-type and mutant p53-bearing tumors.
- To highlight the clinical relevance of subtype-specific approaches for p53-targeted breast cancer treatment.
Main Methods:
- Review of pre-clinical and clinical studies on p53-based breast cancer therapies.
- Analysis of therapeutic strategies including small molecule inhibitors, stapled peptides, PROTACs, and genetic approaches.
- Evaluation of treatment efficacies and limitations in various breast cancer subtypes.
Main Results:
- Diverse p53-targeting therapeutic strategies are under development, including small molecules, peptides, PROTACs, and genetic methods.
- These therapies aim to restore or exploit p53 function in both wild-type and mutant p53 breast cancers.
- Subtype-specific approaches are essential due to the differential prevalence and activity of p53 alterations in breast cancer.
Conclusions:
- Targeting p53, whether wild-type or mutant, offers a promising therapeutic avenue for breast cancer.
- A combination of innovative therapeutic modalities is being explored to overcome p53 inactivation.
- Personalized treatment strategies tailored to p53 status and breast cancer subtype are critical for improving patient outcomes.
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