Abstract 3463: Nuclear localization of S6K is associated with unfavorable disease-free survival in hormone-receptor positive breast cancer cases.
Authors: Kawaguchi-Sakita Nobuko , Mohamed Rafaat Abd El-Aal Bakheet , Sato Fumiaki , Ueno Takayuki , Kawashima Masahiro , Yoshida Noriyuki , Li Wen Zhao , Sugie Tomoharu , Mikami Yoshiki , Saji Shigehira , Inamoto Takashi , Toi Masakazu 
Published: August 2014

[Background& Aim]mTOR signaling pathway (mTOR-S6K-pS6) plays important roles in translation process from RNA to protein and proliferation in many cancers. This pathway works as a hub, where various signals come from growth factors, energy loss and hypoxia and are transmitted to the translation process. Among this pathway, S6K (Ribosomal Protein S6 Kinase) is a key molecule. S6K is phosphorylated not only by mTOR, but also by other molecules. Moreover, S6K itself regulates various other molecules. S6K is the substrate of mTOR, and phospholyrates S6. Among these complicated networks, signal through the mTOR-S6K-S6 pathway contributes to cell. Thus, in breast cancer, this pathway is an important therapeutic target. mTOR pathway functions in the downstream of the HER2-PI3K-Akt signaling and it is known that this pathway is involved in therapeutic resistance, such as hormone resistance and anti-HER2 resistance. However, still many remain unknown about the clinical significance of mTOR related pathways. Therefore we investigated this pathway in breast cancer tissues by immunohistochemistry to find the biomarker for personalized therapy.

[Methods]One-hundred and three formalin-fixed, paraffin-embedded tissue specimens were collected from the Department of Breast Surgery, Kyoto University Hospital between July 2000 and December 2005. The median follow up was 78 months (range, 3-120 months). For mTOR signaling pathway, the expression of S6K, phospho-S6K and phospho-S6 was examined using immunohistochemistry. The correlation between each expression pattern, clinico-pathological characteristics, and prognosis was evaluated statistically.

[Results]In the normal mammary glands, S6K and phospho-S6K were not stained, or stained weakly both in the nucleus and/or the cytoplasm. Phospho-S6 was not detected. In breast cancer cells, S6K and phospho-S6K were detected in the nucleus and/or the cytoplasm as reported previously. Phospho-S6 was detected in the cytoplasm. Staining of these molecules has the heterogeneous pattern. Hormone-receptor negative HR(-) cases had higher expression of phospho-S6 than HR(+) cases (p=0.0276). Cases with weak S6K staining in cytoplasm but strong in the nucleus had shorter DFS (Wilcoxon test, p=0.0304). This trend was clear in the subgroup of HR(+) cases (Wilcoxon test, p=0.0243). There was no significant correlation between the clinical outcome and other expression profile.

[Discussion & Conclusion]It is reported that mTOR regulates nuclear localization of S6K. Although the function of S6K in nucleus is largely unknown, the result of this study suggests that nuclear S6K may play a crucial role in the progression of breast cancer. It is warranted to conduct further investigation. However, nuclear localization of S6K may be a potential biomarker of activated mTOR in breast cancer patients particularly having HR(+) disease.

Citation Format: Nobuko Kawaguchi-Sakita, Rafaat Abd El-Aal Bakheet Mohamed, Fumiaki Sato, Takayuki Ueno, Masahiro Kawashima, Noriyuki Yoshida, Wen Zhao Li, Tomoharu Sugie, Yoshiki Mikami, Shigehira Saji, Takashi Inamoto, Masakazu Toi. Nuclear localization of S6K is associated with unfavorable disease-free survival in hormone-receptor positive breast cancer cases. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3463. doi:10.1158/1538-7445.AM2013-3463