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Upregulation of PKC-δ contributes to antiestrogen resistance in mammary tumor cells

Oncogene volume 24, pages 3166–3176 (2005)Cite this article

Abstract

Acquired resistance to tamoxifen (Tam) in breast cancer patients is a serious therapeutic problem. We have previously reported that protein kinase C-delta (PKC-δ) plays a major role in estrogen (E2)-mediated cell proliferation. To determine if PKC-δ is one of the major alternate signaling pathways that supports cell growth in the presence of Tam, we determined the levels of PKC isoforms in four different models of antiestrogen-resistant cells. Three out of four antiestrogen resistance cell lines (Tam/MCF-7, ICI/MCF-7 and HER-2/MCF-7) expressed significantly high levels of both total and activated PKC-δ levels compared to sensitive cells. Estrogen receptor (ER) alpha content and function are maintained in all the antiestrogen-resistant cell lines. Overexpressing active PKC-δ in Tam-sensitive MCF-7 cells (PKC-δ/MCF-7) led to Tam resistance both in vitro and in vivo. Inhibition of PKC-δ by rottlerin (a relatively specific inhibitor of PKC-δ) or siRNA significantly inhibited estrogen- and Tam-induced growth in antiestrogen-resistant cells. PKC-δ levels are significantly higher in Tam-resistant tumors compared to Tam-sensitive tumors in xenograft model (P<0.05). Taken together, these data suggest that PKC-δ plays a major role in antiestrogen resistance in breast tumor cells and thus provides a new target for treatment.

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Abbreviations

ER:

estrogen receptor

EGFR:

epidermal growth factor receptor

MAPK:

mitogen-activated kinase

PKC:

protein kinase C

Tam:

4-OH-tamoxifen

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Authors and Affiliations

  1. Department of Pathology, Wayne State University School of Medicine, 540 E. Canfield, Detroit, MI, 48201, USA

    Sanaa M Nabha, Selina Glaros, Meng Hong & Kaladhar B Reddy

  2. Department of Tumor Endocrinology, Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, DK-2100, Copenhagen, Denmark

    Anne E Lykkesfeldt

  3. Breast Center, Baylor College of Medicine and the Methodist Hospital, One Baylor Plaza, MS 600, Houston, TX, 77030, USA

    Rachel Schiff & Kent Osborne

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  1. Sanaa M Nabha
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  2. Selina Glaros
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Correspondence to Kaladhar B Reddy.

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This work was supported in part by NIH Grant R01 CA 83964 (to K.B.R.)

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Nabha, S., Glaros, S., Hong, M. et al. Upregulation of PKC-δ contributes to antiestrogen resistance in mammary tumor cells. Oncogene 24, 3166–3176 (2005). https://doi.org/10.1038/sj.onc.1208502

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