title: Activation of mTOR/S6K But Not MAPK Pathways Might Be Associated With High Ki-67, ER(+), and HER2(-) Breast Cancer.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.affiliation: Division of Breast and Endocrine, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Yanai
authors.affiliation: Division of Breast and Endocrine, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Inoue
authors.affiliation: Division of Breast and Endocrine, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yagi
authors.affiliation: Division of Breast and Endocrine, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Arisa
authors.initials: A
authors.lastname: Nishimukai
authors.affiliation: Division of Breast and Endocrine, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Miyagawa
authors.affiliation: Division of Breast and Endocrine, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Murase
authors.affiliation: Division of Breast and Endocrine, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Imamura
authors.affiliation: Division of Breast and Endocrine, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Yukie
authors.initials: Y
authors.lastname: Enomoto
authors.affiliation: Division of Breast and Endocrine, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Takatsuka
authors.affiliation: Department of Surgical Pathology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Department of Surgical Pathology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Hirota
authors.affiliation: Tokushima Breast Care Clinic, Tokushima, Tokushima, Japan.
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Sasa
authors.affiliation: Division of Genome Medicine, Institute for Genome Research, University of Tokushima, Tokushima, Tokushima, Japan.
authors.forename: Toyomasa
authors.initials: T
authors.lastname: Katagiri
authors.affiliation: Division of Breast and Endocrine, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan. Electronic address: ymiyoshi@hyo-med.ac.jp.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Miyoshi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D018275:Carcinoma, Lobular / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000096:biosynthesis*; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000096:biosynthesis / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D019394:Ki-67 Antigen; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C508053:ERBB2 protein, human
keywords: Akt; Breast Cancer; Ki67; PI3K; S6 kinase