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

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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.

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References

  1. Bauer KR, Brown M, Cress RD, Parise CA, Caggiano V (2007) Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California cancer Registry. Cancer 109(9):1721–1728

    Article  PubMed  Google Scholar 

  2. Dent R, Trudeau M, Pritchard KI et al (2007) Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 13(15 Pt 1):4429–4434

    Article  PubMed  Google Scholar 

  3. Liedtke C, Mazouni C, Hess KR et al (2008) Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol 26(8):1275–1281

    Article  PubMed  Google Scholar 

  4. Sorlie T, Perou CM, Tibshirani R et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U.S.A 98(19):10869–10874

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Lehmann BD, Bauer JA, Chen X et al (2011) Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 121(7):2750–2767

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Shah SP, Roth A, Goya R et al (2012) The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature 486(7403):395–399

    CAS  PubMed  Google Scholar 

  7. Wright JD, Lim C (2007) Mechanism of DNA-binding loss upon single-point mutation in p53. J Biosci 32(5):827–839

    Article  CAS  PubMed  Google Scholar 

  8. Oren M, Rotter V (2010) Mutant p53 gain-of-function in cancer. Cold Spring Harb Perspect Biol 2(2):a001107

    Article  PubMed Central  PubMed  Google Scholar 

  9. Xu J, Reumers J, Couceiro JR et al (2011) Gain of function of mutant p53 by coaggregation with multiple tumor suppressors. Nat Chem Biol 7(5):285–295

    Article  CAS  PubMed  Google Scholar 

  10. Di AS, Strano S, Emiliozzi V et al (2006) Gain of function of mutant p53: the mutant p53/NF-Y protein complex reveals an aberrant transcriptional mechanism of cell cycle regulation. Cancer Cell 10(3):191–202

    Article  Google Scholar 

  11. DeGregori J, Johnson DG (2006) Distinct and overlapping roles for E2F family members in transcription, proliferation and apoptosis. Curr Mol Med 6(7):739–748

    CAS  PubMed  Google Scholar 

  12. Engelmann D, Putzer BM (2012) The dark side of E2F1: in transit beyond apoptosis. Cancer Res 72(3):571–575

    Article  CAS  PubMed  Google Scholar 

  13. Phillips AC, Vousden KH (2001) E2F-1 induced apoptosis. Apoptosis 6(3):173–182

    Article  CAS  PubMed  Google Scholar 

  14. Lin WC, Lin FT, Nevins JR (2001) Selective induction of E2F1 in response to DNA damage, mediated by ATM-dependent phosphorylation. Genes Dev 15(14):1833–1844

    PubMed Central  CAS  PubMed  Google Scholar 

  15. Pediconi N, Ianari A, Costanzo A et al (2003) Differential regulation of E2F1 apoptotic target genes in response to DNA damage. Nat Cell Biol 5(6):552–558

    Article  CAS  PubMed  Google Scholar 

  16. Xie Q, Bai Y, Wu J et al (2011) Methylation-mediated regulation of E2F1 in DNA damage-induced cell death. J Recept Signal Transduction Res 31(2):139–146

    CAS  Google Scholar 

  17. Hershko T, Ginsberg D (2004) Up-regulation of Bcl-2 homology 3 (BH3)-only proteins by E2F1 mediates apoptosis. J Biol Chem 279(10):8627–8634

    Article  CAS  PubMed  Google Scholar 

  18. Tonsing-Carter E, Shannon HE, Bailey BJ, Mayo LD, Pollok KE (2013) Blockade of MDM2-mediated signaling in context of DNA damage increases E2F1 expression and enhances cell death in triple-negative breast cancer cells. Cancer Research. 279(10):8627–8634

    Google Scholar 

  19. Gonugunta VK, Miao L, Sareddy GR et al (2014) The social network of PELP1 and its implications in breast and prostate cancers. Endocr Relat Cancer 21(4):T79–T86

    Article  CAS  PubMed  Google Scholar 

  20. Girard BJ, Daniel AR, Lange CA, Ostrander JH (2014) PELP1: a review of PELP1 interactions, signaling, and biology. Mol Cell Endocrinol 382(1):642–651

    Article  CAS  PubMed  Google Scholar 

  21. Habashy HO, Powe DG, Rakha EA et al (2010) The prognostic significance of PELP1 expression in invasive breast cancer with emphasis on the ER-positive luminal-like subtype. Breast Cancer Res Treat 120(3):603–612

    Article  CAS  PubMed  Google Scholar 

  22. Roy S, Chakravarty D, Cortez V et al (2012) Significance of PELP1 in ER-negative breast cancer metastasis. Mol Cancer Res 10(1):25–33

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Nair BC, Nair SS, Chakravarty D et al (2010) Cyclin-dependent kinase-mediated phosphorylation plays a critical role in the oncogenic functions of PELP1. Cancer Res 70(18):7166–7175

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Nair BC, Krishnan SR, Sareddy GR et al (2014) Proline, glutamic acid and leucine-rich protein-1 is essential for optimal p53-mediated DNA damage response. Cell Death Differ 21(9):1409–1418

    Article  CAS  PubMed  Google Scholar 

  25. Mann M, Cortez V, Vadlamudi R (2013) PELP1 oncogenic functions involve CARM1 regulation. Carcinogenesis 34(7):1468–1475

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Bararia D, Trivedi AK, Zada AA et al (2008) Proteomic identification of the MYST domain histone acetyltransferase TIP60 (HTATIP) as a co-activator of the myeloid transcription factor C/EBPalpha. Leukemia 22(4):800–807

    Article  CAS  PubMed  Google Scholar 

  27. Bartek J, Iggo R, Gannon J, Lane DP (1990) Genetic and immunochemical analysis of mutant p53 in human breast cancer cell lines. Oncogene 5(6):893–899

    CAS  PubMed  Google Scholar 

  28. Nigro JM, Baker SJ, Preisinger AC et al (1989) Mutations in the p53 gene occur in diverse human tumour types. Nature 342(6250):705–708

    Article  CAS  PubMed  Google Scholar 

  29. Mann M, Cortez V, Vadlamudi RK (2011) Epigenetics of estrogen receptor signaling: role in hormonal cancer progression and therapy. Cancers (Basel) 3(3):1691–1707

    Article  CAS  Google Scholar 

  30. Sterner DE, Berger SL (2000) Acetylation of histones and transcription-related factors. Microbiol Mol Biol Rev 64(2):435–459

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Bossi G, Lapi E, Strano S et al (2006) Mutant p53 gain of function: reduction of tumor malignancy of human cancer cell lines through abrogation of mutant p53 expression. Oncogene 25(2):304–309

    CAS  PubMed  Google Scholar 

  32. Lim LY, Vidnovic N, Ellisen LW, Leong CO (2009) Mutant p53 mediates survival of breast cancer cells. Br J Cancer 101(9):1606–1612

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Kontaki H, Talianidis I (2010) Lysine methylation regulates E2F1-induced cell death. Mol Cell 39(1):152–160

    Article  CAS  PubMed  Google Scholar 

  34. Nair SS, Nair BC, Cortez V et al (2010) PELP1 is a reader of histone H3 methylation that facilitates oestrogen receptor-alpha target gene activation by regulating lysine demethylase 1 specificity. EMBO Rep 11(6):438–444

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Ueda R, Suzuki T, Mino K et al (2009) Identification of cell-active lysine specific demethylase 1-selective inhibitors. J Am Chem Soc 131(48):17536–17537

    Article  CAS  PubMed  Google Scholar 

  36. Boohaker RJ, Cui X, Stackhouse M, Xu B (2013) ATM-mediated Snail Serine 100 phosphorylation regulates cellular radiosensitivity. Radiother Oncol 108(3):403–408

    Article  CAS  PubMed  Google Scholar 

  37. Sun M, Guo X, Qian X et al (2012) Activation of the ATM-Snail pathway promotes breast cancer metastasis. J Mol Cell Biol 4(5):304–315

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Bertheau P, Lehmann-Che J, Varna M et al (2013) p53 in breast cancer subtypes and new insights into response to chemotherapy. Breast 22(Suppl 2):S27–S29

    Article  PubMed  Google Scholar 

  39. Dobes P, Podhorec J, Coufal O et al (2014) Influence of mutation type on prognostic and predictive values of TP53 status in primary breast cancer patients. Oncol Rep 32:1695–1702

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the NIH/NCI Grant CA095681 (RKV); CPRIT grant DP150096 (RKV; GR); CPRIT pre-doctoral fellow ship grant RP140105 (SK); CPRIT post-doctoral fellowship grant RP140105 (GRS); and the Cancer Therapy and Research Center at the University of Texas Health Science Center at San Antonio through the NCI Cancer Center Support Grant P30CA054174-17.

Conflict of interest

The authors declare no conflicts of interest.

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Authors and Affiliations

  1. Department of Cellular and Structural Biology, UTHSCSA, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA

    Samaya R. Krishnan

  2. Department of Obstetrics and Gynecology, UTHSCSA, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA

    Samaya R. Krishnan, Binoj C. Nair, Gangadhara R. Sareddy, Sudipa Saha Roy & Ratna K. Vadlamudi

  3. Department of Pathology, UTHSCSA, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA

    Mohan Natarajan

  4. Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamohangi-Cho, Sakyo-Ku, Kyoto, 606-0823, Japan

    Takayoshi Suzuki

  5. Department of Pathology, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390, USA

    Yan Peng

  6. Department of Urology, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390, USA

    Ganesh Raj

  7. Cancer Therapy and Research Center, UTHSCSA, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA

    Ratna K. Vadlamudi

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  1. Samaya R. Krishnan
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  2. Binoj C. Nair
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  7. Yan Peng
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Correspondence to Ratna K. Vadlamudi.

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Krishnan, S.R., Nair, B.C., Sareddy, G.R. et al. Novel role of PELP1 in regulating chemotherapy response in mutant p53-expressing triple negative breast cancer cells. Breast Cancer Res Treat 150, 487–499 (2015). https://doi.org/10.1007/s10549-015-3339-x

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  • DOI: https://doi.org/10.1007/s10549-015-3339-x

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