Targeting the PELP1-KDM1 axis as a potential therapeutic strategy for breast cancer

Valerie Cortez, Monica Mann, Seshidhar Tekmal, Takayoshi Suzuki, Naoki Miyata, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Anil K. Sood, Ratna K Vadlamudi

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Introduction: The estrogen receptor (ER) co-regulator proline glutamic acid and leucine-rich protein 1 (PELP1) is a proto-oncogene that modulates epigenetic changes on ER target gene promoters via interactions with lysine-specific histone demethylase 1 (KDM1). In this study, we assessed the therapeutic potential of targeting the PELP1-KDM1 axis in vivo using liposomal (1,2-dioleoyl-sn-glycero-3-phosphatidylcholine; DOPC) siRNA to downregulate PELP1 expression and KDM1 inhibitors, pargyline and N-((1S)-3-(3-(trans-2-aminocyclopropyl)phenoxy)-1-(benzylcarbamoyl)propyl)benzamide using preclinical models.Methods: Preclinical xenograft models were used to test the efficacy of drugs in vivo. Ki-67 and terminal deoxynucleotidyl transferase dUTP nick end-labeling immunohistochemical analysis of epigenetic markers was performed on tumor tissues. The in vitro effect of PELP1-KDM axis blockers was tested using proliferation, reporter gene, chromatin immunoprecipitation and real-time RT-PCR assays. The efficacy of the KDM1 targeting drugs alone or in combination with letrozole and tamoxifen was tested using therapy-resistant model cells.Results: Treatment of ER-positive xenograft-based breast tumors with PELP1-siRNA-DOPC or pargyline reduced tumor volume by 58.6% and 62%, respectively. In a postmenopausal model, in which tumor growth is stimulated solely by local estrogen synthesis, daily pargyline treatment reduced tumor volume by 78%. Immunohistochemical analysis of excised tumors revealed a combined decrease in cellular proliferation, induction of apoptosis and upregulation of inhibitory epigenetic modifications. Pharmacological inhibition of KDM1 in vitro increased inhibitory histone mark dimethylation of histone H3 at lysine 9 (H3K9me2) and decreased histone activation mark acetylation of H3K9 (H3K9Ac) on ER target gene promoters. Combining KDM1 targeting drugs with current endocrine therapies substantially impeded growth and restored sensitivity of therapy-resistant breast cancer cells to treatment.Conclusion: Our results suggest inhibition of PELP1-KDM1-mediated histone modifications as a potential therapeutic strategy for blocking breast cancer progression and therapy resistance.

Original languageEnglish (US)
Article numberR108
JournalBreast Cancer Research
Volume14
Issue number4
DOIs
StatePublished - Jul 19 2012

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Breast Neoplasms
Histone Code
Pargyline
Estrogen Receptors
Epigenomics
Therapeutics
letrozole
Drug Delivery Systems
Tumor Burden
Heterografts
Small Interfering RNA
Histone Demethylases
human PELP1 protein
Neoplasms
Proto-Oncogenes
DNA Nucleotidylexotransferase
Chromatin Immunoprecipitation
Tamoxifen
Acetylation
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Cortez, V., Mann, M., Tekmal, S., Suzuki, T., Miyata, N., Rodriguez-Aguayo, C., ... Vadlamudi, R. K. (2012). Targeting the PELP1-KDM1 axis as a potential therapeutic strategy for breast cancer. Breast Cancer Research, 14(4), [R108]. https://doi.org/10.1186/bcr3229

Targeting the PELP1-KDM1 axis as a potential therapeutic strategy for breast cancer. / Cortez, Valerie; Mann, Monica; Tekmal, Seshidhar; Suzuki, Takayoshi; Miyata, Naoki; Rodriguez-Aguayo, Cristian; Lopez-Berestein, Gabriel; Sood, Anil K.; Vadlamudi, Ratna K.

In: Breast Cancer Research, Vol. 14, No. 4, R108, 19.07.2012.

Research output: Contribution to journalArticle

Cortez, V, Mann, M, Tekmal, S, Suzuki, T, Miyata, N, Rodriguez-Aguayo, C, Lopez-Berestein, G, Sood, AK & Vadlamudi, RK 2012, 'Targeting the PELP1-KDM1 axis as a potential therapeutic strategy for breast cancer', Breast Cancer Research, vol. 14, no. 4, R108. https://doi.org/10.1186/bcr3229
Cortez V, Mann M, Tekmal S, Suzuki T, Miyata N, Rodriguez-Aguayo C et al. Targeting the PELP1-KDM1 axis as a potential therapeutic strategy for breast cancer. Breast Cancer Research. 2012 Jul 19;14(4). R108. https://doi.org/10.1186/bcr3229
Cortez, Valerie ; Mann, Monica ; Tekmal, Seshidhar ; Suzuki, Takayoshi ; Miyata, Naoki ; Rodriguez-Aguayo, Cristian ; Lopez-Berestein, Gabriel ; Sood, Anil K. ; Vadlamudi, Ratna K. / Targeting the PELP1-KDM1 axis as a potential therapeutic strategy for breast cancer. In: Breast Cancer Research. 2012 ; Vol. 14, No. 4.
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AU - Rodriguez-Aguayo, Cristian

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N2 - Introduction: The estrogen receptor (ER) co-regulator proline glutamic acid and leucine-rich protein 1 (PELP1) is a proto-oncogene that modulates epigenetic changes on ER target gene promoters via interactions with lysine-specific histone demethylase 1 (KDM1). In this study, we assessed the therapeutic potential of targeting the PELP1-KDM1 axis in vivo using liposomal (1,2-dioleoyl-sn-glycero-3-phosphatidylcholine; DOPC) siRNA to downregulate PELP1 expression and KDM1 inhibitors, pargyline and N-((1S)-3-(3-(trans-2-aminocyclopropyl)phenoxy)-1-(benzylcarbamoyl)propyl)benzamide using preclinical models.Methods: Preclinical xenograft models were used to test the efficacy of drugs in vivo. Ki-67 and terminal deoxynucleotidyl transferase dUTP nick end-labeling immunohistochemical analysis of epigenetic markers was performed on tumor tissues. The in vitro effect of PELP1-KDM axis blockers was tested using proliferation, reporter gene, chromatin immunoprecipitation and real-time RT-PCR assays. The efficacy of the KDM1 targeting drugs alone or in combination with letrozole and tamoxifen was tested using therapy-resistant model cells.Results: Treatment of ER-positive xenograft-based breast tumors with PELP1-siRNA-DOPC or pargyline reduced tumor volume by 58.6% and 62%, respectively. In a postmenopausal model, in which tumor growth is stimulated solely by local estrogen synthesis, daily pargyline treatment reduced tumor volume by 78%. Immunohistochemical analysis of excised tumors revealed a combined decrease in cellular proliferation, induction of apoptosis and upregulation of inhibitory epigenetic modifications. Pharmacological inhibition of KDM1 in vitro increased inhibitory histone mark dimethylation of histone H3 at lysine 9 (H3K9me2) and decreased histone activation mark acetylation of H3K9 (H3K9Ac) on ER target gene promoters. Combining KDM1 targeting drugs with current endocrine therapies substantially impeded growth and restored sensitivity of therapy-resistant breast cancer cells to treatment.Conclusion: Our results suggest inhibition of PELP1-KDM1-mediated histone modifications as a potential therapeutic strategy for blocking breast cancer progression and therapy resistance.

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