Novel role of PELP1 in regulating chemotherapy response in mutant p53-expressing triple negative breast cancer cells

Samaya R. Krishnan, Binoj C. Nair, Gangadhara R. Sareddy, Sudipa Saha Roy, Mohan Natarajan, Takayoshi Suzuki, Yan Peng, Ganesh Raj, Ratna K. Vadlamudi

Research output: Contribution to journalArticle

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Abstract

Triple-negative breast cancer (TNBC), the most aggressive breast cancer subtype, occurs in younger women and is associated with poor prognosis. Gain-of-function mutations in TP53 are a frequent occurrence in TNBC and have been demonstrated to repress apoptosis and up-regulate cell cycle progression. Even though TNBC responds to initial chemotherapy, resistance to chemotherapy develops and is a major clinical problem. Tumor recurrence eventually occurs and most patients die from their disease. An urgent need exists to identify molecular-targeted therapies that can enhance chemotherapy response. In the present study, we report that targeting PELP1, an oncogenic co-regulator molecule, could enhance the chemotherapeutic response of TNBC through the inhibition of cell cycle progression and activation of apoptosis. We demonstrate that PELP1 interacts with MTp53, regulates its recruitment, and alters epigenetic marks at the target gene promoters. PELP1 knockdown reduced MTp53 target gene expression, resulting in decreased cell survival and increased apoptosis upon genotoxic stress. Mechanistic studies revealed that PELP1 depletion contributes to increased stability of E2F1, a transcription factor that regulates both cell cycle and apoptosis in a context-dependent manner. Further, PELP1 regulates E2F1 stability in a KDM1A-dependent manner, and PELP1 phosphorylation at the S1033 residue plays an important role in mediating its oncogenic functions in TNBC cells. Accordingly, depletion of PELP1 increased the expression of E2F1 target genes and reduced TNBC cell survival in response to genotoxic agents. PELP1 phosphorylation was significantly greater in the TNBC tumors than in the other subtypes of breast cancer and in the normal tissues. These findings suggest that PELP1 is an important molecular target in TNBC, and that PELP1-targeted therapies may enhance response to chemotherapies.

Original languageEnglish (US)
Pages (from-to)487-499
Number of pages13
JournalBreast Cancer Research and Treatment
Volume150
Issue number3
DOIs
StatePublished - Apr 1 2015

Fingerprint

Triple Negative Breast Neoplasms
Drug Therapy
Apoptosis
Cell Cycle
Breast Neoplasms
S 1033
Cell Survival
E2F1 Transcription Factor
Phosphorylation
Molecular Targeted Therapy
Epigenomics
Genes
DNA Damage
Up-Regulation
Gene Expression
Recurrence
Mutation

Keywords

  • Coregulator
  • DNA damage response
  • E2F1
  • Oncogene
  • p53
  • PELP1
  • TNBC

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Krishnan, S. R., Nair, B. C., Sareddy, G. R., Roy, S. S., Natarajan, M., Suzuki, T., ... Vadlamudi, R. K. (2015). Novel role of PELP1 in regulating chemotherapy response in mutant p53-expressing triple negative breast cancer cells. Breast Cancer Research and Treatment, 150(3), 487-499. https://doi.org/10.1007/s10549-015-3339-x

Novel role of PELP1 in regulating chemotherapy response in mutant p53-expressing triple negative breast cancer cells. / Krishnan, Samaya R.; Nair, Binoj C.; Sareddy, Gangadhara R.; Roy, Sudipa Saha; Natarajan, Mohan; Suzuki, Takayoshi; Peng, Yan; Raj, Ganesh; Vadlamudi, Ratna K.

In: Breast Cancer Research and Treatment, Vol. 150, No. 3, 01.04.2015, p. 487-499.

Research output: Contribution to journalArticle

Krishnan, Samaya R. ; Nair, Binoj C. ; Sareddy, Gangadhara R. ; Roy, Sudipa Saha ; Natarajan, Mohan ; Suzuki, Takayoshi ; Peng, Yan ; Raj, Ganesh ; Vadlamudi, Ratna K. / Novel role of PELP1 in regulating chemotherapy response in mutant p53-expressing triple negative breast cancer cells. In: Breast Cancer Research and Treatment. 2015 ; Vol. 150, No. 3. pp. 487-499.
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