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Coexistence of the loss of heterozygosity at the PTEN locus and HER2 overexpression enhances the Akt activity thus leading to a negative progesterone receptor expression in breast carcinoma

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Abstract

Serine/threonine kinase Akt/PKB is known to regulate divergent cellular processes, including apoptosis, proliferation, differentiation, and metabolism. Akt is activated by a variety of stimuli, through such growth factor receptors as HER2, in phosphoinositide-3-OH kinase (PI3K)-dependent manner. A loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) function also activates Akt. It has recently been shown that Akt activation is associated with a worse outcome among endocrine treated breast cancer patients and that it also inhibits the progesterone receptor (PR) expression via the PI3K/Akt pathway in breast cancer cells. Therefore, the PI3K/Akt signaling pathway has recently attracted considerable attention as a new target for effective therapeutic strategies. In the present study, we investigated the relationship between Akt activation and either HER2 overexpression or PTEN gene alteration, as well as the PR expression. We analyzed the incidence of LOH at the PTEN locus in 138 breast cancer patients, using our new system for microsatellite analysis, called high-resolution fluorescent microsatellite analysis (HRFMA). We showed Akt activation to significantly correlate with HER2 overexpression or LOH at the PTEN gene locus while inversely correlating with the PR expression. In addition, when LOH at the PTEN gene locus and HER2 overexpression occurred simultaneously, the incidence of Akt activation and reduced PR expression was significant. The association between Akt activation and PR negative expression was observed even in the ER-positive cases. Our results suggest that simultaneous PTEN LOH and HER2 overexpression enhances Akt activation and may thus lead to a negative PR expression.

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Acknowledgements

We are grateful to Ms. Y. Kubota, Ms. N. Nakamura, Y. Ms. T. Shishino, Ms. K. Yamashita and Ms. N. Makikusa for their valuable technical assistance.

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Authors and Affiliations

  1. Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan

    Eriko Tokunaga, Eiji Oki, Yasue Kimura, Akinori Egashira, Kojiro Nishida, Tadashi Koga, Masaru Morita, Yoshihiro Kakeji & Yoshihiko Maehara

  2. Institute for Clinical Research, National Kyushu Cancer Center, Notame 3-1-1, Minami-ku, Fukuoka, 811-1395, Japan

    Takeharu Yamanaka

Authors
  1. Eriko Tokunaga
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  2. Eiji Oki
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  3. Yasue Kimura
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  4. Takeharu Yamanaka
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  5. Akinori Egashira
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  6. Kojiro Nishida
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  7. Tadashi Koga
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  8. Masaru Morita
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  9. Yoshihiro Kakeji
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  10. Yoshihiko Maehara
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Correspondence to Eriko Tokunaga.

Additional information

This study was supported by grants from the Ministry of Education, Culture, Sports Science, and Technology of Japan.

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Tokunaga, E., Oki, E., Kimura, Y. et al. Coexistence of the loss of heterozygosity at the PTEN locus and HER2 overexpression enhances the Akt activity thus leading to a negative progesterone receptor expression in breast carcinoma. Breast Cancer Res Treat 101, 249–257 (2007). https://doi.org/10.1007/s10549-006-9295-8

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  • DOI: https://doi.org/10.1007/s10549-006-9295-8

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