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Breast Cancer

, Volume 15, Issue 1, pp 73–78 | Cite as

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

  • Teruhiko FujiiEmail author
  • Goro Yokoyama
  • Hiroki Takahashi
  • Roka Namoto
  • Shino Nakagawa
  • Uhi Toh
  • Masayoshi Kage
  • Kazuo Shirouzu
  • Michihiko Kuwano
Conference Paper Symposium: Molecular target therapy

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.

Keywords

Breast cancer Molecular targeting Protein kinase C Cap43 YB-1 

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

Notes

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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Copyright information

© The Japanese Breast Cancer Society 2007

Authors and Affiliations

  • Teruhiko Fujii
    • 1
    • 2
    • 3
    Email author
  • Goro Yokoyama
    • 1
    • 3
  • Hiroki Takahashi
    • 1
    • 3
  • Roka Namoto
    • 4
  • Shino Nakagawa
    • 1
  • Uhi Toh
    • 1
  • Masayoshi Kage
    • 5
  • Kazuo Shirouzu
    • 1
  • Michihiko Kuwano
    • 2
  1. 1.Department of SurgeryKurume UniversityFukuokaJapan
  2. 2.Center for Innovative Cancer Therapy of the 21st Century COE Program for Medical ScienceKurume UniversityFukuokaJapan
  3. 3.Department of SurgeryClinical Research Institute, National Hospital Organization Kyushu Medical CancerFukuokaJapan
  4. 4.Department of RadiologyClinical Research Institute, National Hospital Organization Kyushu Medical CancerFukuokaJapan
  5. 5.Department of PathologyKurume UniversityFukuokaJapan

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