HER3 and downstream pathways are involved in colonization of brain metastases from breast cancer

被引：114

作者：

Da Silva, Leonard ^{[1
,2
,3
]}

Simpson, Peter T. ^{[1
,2
]}

Smart, Chanel E. ^{[1
,2
]}

Cocciardi, Sibylle ^{[2
]}

Waddell, Nic ^{[2
]}

Lane, Annette ^{[1
]}

Morrison, Brian J. ^{[2
,4
]}

Vargas, Ana Cristina ^{[1
]}

Healey, Sue ^{[2
]}

Beesley, Jonathan ^{[2
]}

Pakkiri, Pria ^{[1
]}

Parry, Suzanne ^{[1
,2
]}

Kurniawan, Nyoman ^{[5
]}

Reid, Lynne ^{[1
,2
]}

Keith, Patricia ^{[1
,2
]}

Faria, Paulo ^{[6
,7
]}

Pereira, Emilio ^{[8
]}

Skalova, Alena ^{[9
]}

Bilous, Michael ^{[10
]}

Balleine, Rosemary L. ^{[11
]}

Do, Hongdo ^{[12
]}

Dobrovic, Alexander ^{[12
]}

Fox, Stephen ^{[12
]}

Franco, Marcello ^{[3
]}

Reynolds, Brent ^{[13
]}

Khanna, Kum Kum ^{[2
]}

Cummings, Margaret ^{[1
,2
]}

Chenevix-Trench, Georgia ^{[2
]}

Lakhani, Sunil R. ^{[1
,2
,14
]}

机构：

[1] Univ Queensland, Clin Res Ctr, Brisbane, Qld 4029, Australia

[2] Queensland Inst Med Res, Brisbane, Qld 4006, Australia

[3] Univ Fed Sao Paulo, EPM, Dept Anat Patol, BR-04024000 Sao Paulo, Brazil

[4] Griffith Univ, Brisbane, Qld 4011, Australia

[5] Univ Queensland, Ctr Magnet Resonance, Brisbane, Qld 4072, Australia

[6] Eijkman Inst, Jakarta 10430, Indonesia

[7] Inst Nacl Canc, Dept Patol, BR-20230130 Rio De Janeiro, Brazil

[8] Lab Salomao & Zoppi, Dept Patol, BR-04104000 Sao Paulo, Brazil

[9] Charles Univ Prague, Fac Med, Dept Pathol, Plzen 30605, Czech Republic

[10] Univ Sydney, Inst Clin Pathol & Med Res, Sydney W Area Hlth Serv, Sydney, NSW 2145, Australia

[11] Univ Sydney, Westmead Millennium Inst, Sydney W Area Hlth Serv, Sydney, NSW 2145, Australia

[12] Peter MacCallum Canc Ctr, Dept Pathol, Melbourne, Vic 3002, Australia

[13] Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia

[14] Royal Brisbane & Womens Hosp, Brisbane, Qld 4029, Australia

来源：

BREAST CANCER RESEARCH | 2010年 / 12卷 / 04期

关键词：

NEUREGULIN EXPRESSION; TRASTUZUMAB; CELLS; LANDSCAPES; GENES; COMPLEX; BINDING; PROTEIN; ASSAY; NEU;

D O I：

10.1186/bcr2603

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Introduction: Metastases to the brain from breast cancer have a high mortality, and basal-like breast cancers have a propensity for brain metastases. However, the mechanisms that allow cells to colonize the brain are unclear. Methods: We used morphology, immunohistochemistry, gene expression and somatic mutation profiling to analyze 39 matched pairs of primary breast cancers and brain metastases, 22 unmatched brain metastases of breast cancer, 11 non-breast brain metastases and 6 autopsy cases of patients with breast cancer metastases to multiple sites, including the brain. Results: Most brain metastases were triple negative and basal-like. The brain metastases over-expressed one or more members of the HER family and in particular HER3 was significantly over-expressed relative to matched primary tumors. Brain metastases from breast and other primary sites, and metastases to multiple organs in the autopsied cases, also contained somatic mutations in EGFR, HRAS, KRAS, NRAS or PIK3CA. This paralleled the frequent activation of AKT and MAPK pathways. In particular, activation of the MAPK pathway was increased in the brain metastases compared to the primary tumors. Conclusions: Deregulated HER family receptors, particularly HER3, and their downstream pathways are implicated in colonization of brain metastasis. The need for HER family receptors to dimerize for activation suggests that tumors may be susceptible to combinations of anti-HER family inhibitors, and may even be effective in the absence of HER2 amplification (that is, in triple negative/basal cancers). However, the presence of activating mutations in PIK3CA, HRAS, KRAS and NRAS suggests the necessity for also specifically targeting downstream molecules.

引用

页数：13

共 57 条

[1] Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth [J].