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Preclinical studies of molecular-targeting diagnostic and therapeutic strategies against breast cancer

Abstract

We have investigated protein kinase C (PKC) signaling, a putative differentiation-related and metastasis suppressor gene Cap43/NDRG1/Drg-1, and Y-box binding protein-1 (YB-1) to identify new molecular targeting for breast cancer. PKC is a family of serine/threonine kinases that is involved in the regulation of cell growth. We have demonstrated that PKC caused G1 arrest in a breast cancer cell line through a mechanism involving a PKC–ERK MAPK–JNK–Rb protein signaling pathway. We have also characterized a novel mechanism through which all-trans retinoic acid (ATRA) and antineoplaston, anticancer drug, caused cell growth inhibition in breast cancer cells through effects on intracellular pathways. ATRA decreased the expression of PKCα, as well as reduced ERK MAPK phosphorylation, and consequently caused G1 arrest. Antineoplaston caused the down-regulation of PKCα protein expression, resulting in inhibition of ERK MAPK phosphorylation, with resultant inhibition of Rb phosphorylation leading to G1 arrest. PKC signaling represents a promising target for development of novel therapeutic agents. Cap43 is known as N-myc downstream-regulated gene 1 (NDRG1). Treatment with estradiol (E2) significantly decreased the expression of Cap43 in ER-α-positive breast cancer cell lines. Co-administration of tamoxifen abrogated the E2-induced downregulation of Cap43 in ER-α-positive cell lines. These results suggested that Cap43 may hold the potential of being a molecular marker to determine the therapeutic efficacy of anti-estrogenic anticancer agents in breast cancer. YB-1 is a member of the cold shock domain protein family. The expression of nuclear YB-1 was correlated with HER2 positively in clinical specimens of human breast cancer. Immunostaining studies showed that nuclear YB-1 expression was an independent prognostic factor of overall survival. Expression of nuclear YB-1 played an essential role in acquirement of malignant characteristics through HER2-dependent pathways in breast cancer patients. PKC, Cap43 and YB-1 may be useful in new molecular-targeting diagnosis and therapeutics in breast cancer.

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Abbreviations

PKC:

Protein kinase C

NDRG1:

N-myc downstream-regulated gene 1

Drg-1:

Differentiation-related gene-1

YB-1:

Y-box binding protein-1

MAPK:

Mitogen-activated protein kinase

ERK:

Extracellular signal-regulated kinase

JNK:

c-Jun NH2-terminal kinase

Rb:

Retinoblastoma

ATRA:

All-trans retinoic acid

E2 :

Estradiol

VEGF:

Vascular endothelial growth factor

EGFR:

Epidermal growth factor receptor

DAG:

Diacylglycerol

PMA:

Phorbol 12-myristate 13 acetate

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Acknowledgments

We would like to thank Yuji Basaki, Abbas Fotovati, Anna Nakamura, and Akihiko Kawahara for invaluable help in completing the studies presented in this article.

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Correspondence to Teruhiko Fujii.

Additional information

This article is based on a presentation delivered at Symposium 3, “Molecular target therapy: basics and clinical application,” held on 30 June 2007 at the 15th Annual Meeting of the Japanese Breast Cancer Society in Yokohama.

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Fujii, T., Yokoyama, G., Takahashi, H. et al. Preclinical studies of molecular-targeting diagnostic and therapeutic strategies against breast cancer. Breast Cancer 15, 73–78 (2008). https://doi.org/10.1007/s12282-007-0015-y

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Keywords

  • Breast cancer
  • Molecular targeting
  • Protein kinase C
  • Cap43
  • YB-1