Deregulation of the EGFR/PI3K/PTEN/Akt/mTORC1 pathway in breast cancer: possibilities for therapeutic intervention

被引：232

作者：

Davis, Nicole M. ^{[1
]}

Sokolosky, Melissa ^{[1
]}

Stadelman, Kristin ^{[1
]}

Abrams, Stephen L. ^{[1
]}

Libra, Massimo ^{[2
]}

Candido, Saverio ^{[2
]}

Nicoletti, Ferdinando ^{[2
]}

Polesel, Jerry ^{[3
]}

Maestro, Roberta ^{[4
]}

D'Assoro, Antonino ^{[5
]}

Drobot, Lyudmyla ^{[6
]}

Rakus, Dariusz ^{[7
]}

Gizak, Agnieszka ^{[7
]}

Laidler, Piotr ^{[8
]}

Dulinska-Litewka, Joanna ^{[8
]}

Basecke, Joerg ^{[9
]}

Mijatovic, Sanja ^{[10
]}

Maksimovic-Ivanic, Danijela ^{[10
]}

Montalto, Giuseppe ^{[11
,12
]}

Cervello, Melchiorre ^{[12
]}

Fitzgerald, Timothy L. ^{[13
]}

Demidenko, Zoya N. ^{[14
]}

Martelli, Alberto M. ^{[15
]}

Cocco, Lucio ^{[15
]}

Steelman, Linda S. ^{[1
]}

McCubrey, James A. ^{[1
]}

机构：

[1] E Carolina Univ, Brody Sch Med, Dept Microbiol & Immunol, Greenville, NC 27858 USA

[2] Univ Catania, Dept Biomed Sci, Catania, Italy

[3] IRCCS, Ctr Riferimento Oncol, Unit Epidemiol & Biostat, Aviano, Italy

[4] Natl Canc Inst, CRO IRCCS, Aviano, Pordenone, Italy

[5] Mayo Clin, Coll Med, Dept Biochem & Mol Biol, Rochester, MN USA

[6] Natl Acad Sci Ukraine, Palladin Inst Biochem, Kiev, Ukraine

[7] Univ Wroclaw, Inst Expt Biol, Dept Anim Mol Physiol, PL-50138 Wroclaw, Poland

[8] Jagiellonian Univ, Coll Med, Chair Med Biochem, Krakow, Poland

[9] Univ Gottingen, Dept Med, D-37073 Gottingen, Germany

[10] Univ Belgrade, Inst Biol Res Sinisa Stankovic, Dept Immunol, Belgrade, Serbia

[11] Univ Palermo, Biomed Dept Internal Med & Specialties, Palermo, Italy

[12] CNR, Ist Biomed & Immunol Mol Alberto Monroy, Palermo, Italy

[13] E Carolina Univ, Brody Sch Med, Dept Surg, Greenville, NC 27858 USA

[14] Roswell Pk Canc Inst, Dept Cell Stress Biol, Buffalo, NY 14263 USA

[15] Univ Bologna, Dipartimento Sci Biomed & Neuromotorie, Bologna, Italy

来源：

ONCOTARGET | 2014年 / 5卷 / 13期

关键词：

Targeted Therapy; Therapy Resistance; Mutations; PI3K; mTOR; rapamycin; GROWTH-FACTOR RECEPTOR; ACUTE LYMPHOBLASTIC-LEUKEMIA; TO-MESENCHYMAL TRANSITION; OXIDATIVE MITOCHONDRIAL METABOLISM; GLYCOGEN-SYNTHASE KINASE-3-BETA; HOMOLOGY-DIRECTED REPAIR; SPORADIC BREAST; STEM-CELLS; TUMOR-SUPPRESSOR; PRIMARY RESISTANCE;

D O I：

10.18632/oncotarget.2209

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

The EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway plays prominent roles in malignant transformation, prevention of apoptosis, drug resistance and metastasis. The expression of this pathway is frequently altered in breast cancer due to mutations at or aberrant expression of: HER2, ERalpha, BRCA1, BRCA2, EGFR1, PIK3CA, PTEN, TP53, RB as well as other oncogenes and tumor suppressor genes. In some breast cancer cases, mutations at certain components of this pathway (e.g., PIK3CA) are associated with a better prognosis than breast cancers lacking these mutations. The expression of this pathway and upstream HER2 has been associated with breast cancer initiating cells (CICs) and in some cases resistance to treatment. The anti-diabetes drug metformin can suppress the growth of breast CICs and herceptin-resistant HER2+ cells. This review will discuss the importance of the EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway primarily in breast cancer but will also include relevant examples from other cancer types. The targeting of this pathway will be discussed as well as clinical trials with novel small molecule inhibitors. The targeting of the hormone receptor, HER2 and EGFR1 in breast cancer will be reviewed in association with suppression of the EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway.

引用

页码：4603 / 4650

页数：48

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