Activation of mTOR/S6K But Not MAPK Pathways Might Be Associated With High Ki-67, ER(+), and HER2(-) Breast Cancer.

Abstract

UNLABELLED:

We determined the activation of the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways in 108 cases of estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancer with high and low Ki-67 expression. The expression levels of Ki-67, p53, phosphorylated MAPK (pMAPK), and protein S6 (pS6; downstream molecule of PI3K/Akt/mammalian target of rapamycin/S6 kinase pathway) were determined immunohistochemically. pS6 positivity, but not pMAPK positivity, was significantly associated with the high Ki-67 expression subset.

BACKGROUND:

Evaluation of luminal A and luminal B characteristics of estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer is considered important. Although the phosphoinositide 3 kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways are thought to be involved in the luminal B subtype, the details of their contribution to breast cancer remain unclear.

MATERIALS AND METHODS:

We determined the activation of these pathways (phosphorylated MAPK [pMAPK] and protein S6 [pS6; a downstream molecule of PI3K/Akt/mammalian target of rapamycin (mTOR)/S6 kinase (S6K)]) in 108 ER(+), HER2(-) breast cancer cases with high and low Ki-67 expression. The ER, progesterone receptor (PgR), Ki-67, p53 expression levels were also determined immunohistochemically. The cutoff value for Ki-67 was set at 15%.

RESULTS:

A significantly greater percentage of cancer cases with high Ki-67 expression showed pS6 positivity than did those with low Ki-67 expression (53.2% vs. 19.7%; P = .0003). No significant differences were found between the cases with high and low expression levels were detected for p53 (23.4% vs. 11.5%; P = .12) or pMAPK (36.2% vs. 34.4%; P = .85) positivity. Multivariate analysis showed that pS6 positivity (odds ratio 5.16, 95% confidence interval 1.95-13.63; P = .0009), nuclear grade 2 and 3, and low PgR expression (≤ 20%) were independently associated with the high Ki-67 subset.

CONCLUSION:

From our findings, we have concluded that the pS6 expression level is associated with the characteristics of breast cancer with high Ki-67 expression. Because these associations were observed, irrespective of menopausal status, the biologic difference seems to be less affected by estrogen signaling than by activation of S6 protein, especially in terms of proliferation. Our findings have also indicated that targeting the mTOR/S6K pathway might be a useful strategy for the treatment of ER(+)/HER2(-) breast cancer with high Ki-67 expression.

• Authors: Ayako Yanai, Natsuko Inoue, Tomoko Yagi, Arisa Nishimukai, Yoshimasa Miyagawa, Keiko Murase, Michiko Imamura, Yukie Enomoto, Yuichi Takatsuka, Takahiro Watanabe, Seiichi Hirota, Mitsunori Sasa, Toyomasa Katagiri, Yasuo Miyoshi
• Journal: Clinical breast cancer (Clin Breast Cancer) Vol. 15 Issue 3 Pg. 197-203 (Jun 2015) ISSN: 1938-0666 [Electronic] United States
• PMID: 25600244 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Ki-67 Antigen
• Receptors, Estrogen
• MTOR protein, human
• ERBB2 protein, human
• Receptor, ErbB-2
• Ribosomal Protein S6 Kinases
• TOR Serine-Threonine Kinases
• Mitogen-Activated Protein Kinases

Topics

• Adult
• Aged
• Aged, 80 and over
• Breast Neoplasms (metabolism, pathology, surgery)
• Carcinoma, Ductal, Breast (metabolism, pathology, surgery)
• Carcinoma, Lobular (metabolism, pathology, surgery)
• Female
• Humans
• Ki-67 Antigen (biosynthesis)
• Middle Aged
• Mitogen-Activated Protein Kinases (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation
• Receptor, ErbB-2 (metabolism)
• Receptors, Estrogen (metabolism)
• Ribosomal Protein S6 Kinases (biosynthesis, metabolism)
• Signal Transduction
• TOR Serine-Threonine Kinases (metabolism)