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Identification of PUMA as an estrogen target gene that mediates the apoptotic response to tamoxifen in human breast cancer cells and predicts patient outcome and tamoxifen responsiveness in breast cancer

Oncogene volume 30, pages 3186–3197 (2011)Cite this article

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Abstract

Recognition of the pivotal role of estrogen in the aetiology of breast cancer has led to the development of antiestrogens (AE), such as tamoxifen (TAM) as effective therapies for the treatment and prevention of this disease. However, despite their widespread clinical efficacy, response to AEs is often short-lived, and acquired or innate therapeutic resistance remains a major obstacle in the successful treatment of breast cancer. Thus, delineating the intracellular pathways that mediate the cellular response to estrogen could potentially lead to new, more effective approaches to the treatment of breast cancer, particularly endocrine-resistant disease. Here, we have identified the BCL-2 homology 3 (BH3)-only, pro-apoptotic regulator, PUMA (p53 upregulated modulator of apoptosis) as an estrogen target gene that is acutely downregulated in response to estrogen in breast cancer cell lines, independently of their p53 status. PUMA is transcriptionally upregulated following treatment with TAM, and knock down of PUMA expression in these cells attenuates the apoptotic response to TAM. Furthermore, low PUMA expression in breast carcinomas is significantly associated with breast cancer-specific death (P=0.0014 and P=0.0115, for mRNA and protein, respectively), and worse outcome in TAM-treated patients (mRNA, P=1.49e-05). These findings suggest that the dysregulation of apoptotic signaling pathways such as those executed through PUMA, can significantly impact on both the progression and therapeutic responsiveness of breast cancer. Moreover, they provide a convincing rationale for exploring new therapeutic approaches involving endocrine and non-endocrine therapies that target apoptotic pathways as an effective strategy for tackling endocrine refractory disease.

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Abbreviations

AE:

anti-estrogen

TAM:

tamoxifen

FCS:

fetal calf serum

4-OHT:

4-hydroxytamoxifen

ER:

estrogen receptor

ChIP:

chromatin immunoprecipitation

TMA:

tissue microarray

PR:

progesterone receptor

EGFR:

epidermal growth factor receptor

ERE:

estrogen response element

HER2:

human epidermal growth factor receptor 2

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Acknowledgements

This research was supported by a National Health and Medical Research Council (NHMRC) of Australia Program Grant 535903, the Australian Cancer Research Fund, the RT Hall Trust, the Petre Foundation, a Cancer Institute NSW Career Development and Support Fellowship (AJB), Cancer Institute NSW Clinical Research Fellowships (EKAM and SAO’T) and an NHMRC health professional training fellowship (SAO’T).

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Author notes

  1. C G Roberts and E K A Millar: These authors contributed equally to this work.

Authors and Affiliations

  1. Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia

    C G Roberts, E K A Millar, S A O'Toole, C M McNeil, G M Lehrbach, M Pinese, P Tobelmann, R A McCloy, E A Musgrove, R L Sutherland & A J Butt

  2. Department of Anatomical Pathology, South Eastern Area Laboratory Service, St George Hospital, Kogarah, New South Wales, Australia

    E K A Millar

  3. School of Medicine, University of Western Sydney, Campbelltown, New South Wales, Australia

    E K A Millar, E A Musgrove, R L Sutherland & A J Butt

  4. St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia

    S A O'Toole

  5. Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia

    S A O'Toole

  6. Central Clinical School, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia

    S A O'Toole

  7. Department of Medical Oncology, Westmead Hospital, Westmead, New South Wales, Australia

    C M McNeil

  8. Western Clinical School, University of Sydney, Sydney, New South Wales, Australia

    C M McNeil

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  1. C G Roberts
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  6. M Pinese
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Correspondence to A J Butt.

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Roberts, C., Millar, E., O'Toole, S. et al. Identification of PUMA as an estrogen target gene that mediates the apoptotic response to tamoxifen in human breast cancer cells and predicts patient outcome and tamoxifen responsiveness in breast cancer. Oncogene 30, 3186–3197 (2011). https://doi.org/10.1038/onc.2011.36

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