SREBP1 drives Keratin-80-dependent cytoskeletal changes and invasive behavior in endocrine-resistant ERα breast cancer

被引：58

作者：

Perone, Ylenia ^{[1
]}

Farrugia, Aaron J. ^{[2
]}

Meira, Alba Rodriguez ^{[1
,13
]}

Gyorffy, Balazs ^{[3
,4
]}

Ion, Charlotte ^{[1
]}

Uggetti, Andrea ^{[5
]}

Chronopoulos, Antonios ^{[6
]}

Marrazzo, Pasquale ^{[7
]}

Faronato, Monica ^{[8
]}

Shousha, Sami ^{[9
]}

Davies, Claire ^{[10
]}

Steel, Jennifer H. ^{[10
]}

Patel, Naina ^{[10
]}

Hernandez, Armando del Rio ^{[6
]}

Coombes, Charles ^{[1
]}

Pruneri, Giancarlo ^{[11
,12
]}

Lim, Adrian ^{[1
]}

Calvo, Fernando ^{[2
,14
]}

Magnani, Luca ^{[1
]}

机构：

[1] Imperial Coll London, Dept Surg & Canc, London, England

[2] Inst Canc Res, Div Canc Biol, Tumour Microenvironm Team, London, England

[3] Hungarian Acad Sci, Inst Enzymol, MTA TTK Lendulet Canc Biomarker Res Grp, Budapest, Hungary

[4] Semmelweis Univ, Dept Pediat 2, Budapest, Hungary

[5] European Inst Oncol, Milan, Italy

[6] Imperial Coll London, Dept Bioengn, Fac Engn, London, England

[7] Univ Bologna, Alma Mater Studiorum, Dept Life Qual Studies, Rimini, Italy

[8] Imperial Coll London, Dept Chem, London, England

[9] Imperial Coll London, Charing Cross Hosp NHS Trust, Dept Histopathol, London, England

[10] Imperial Coll London, Dept Surg & Canc, ECMC Imperial Coll, London, England

[11] Fdn IRCCS Ist Nazl Tumori, Dept Pathol, Milan, Italy

[12] Univ Milan, Sch Med, Milan, Italy

[13] Univ Oxford, Weatherall Inst Mol Med, Haematopoiet Stem Cell Biol Lab, MRC Mol Haematol Unit, Oxford, England

[14] Inst Biomed & Biotecnol Cantabria, Santander, Spain

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

关键词：

GENE-EXPRESSION; THERAPY; CHOLESTEROL; PROGRESSION; TAMOXIFEN; MIGRATION; CELLS;

D O I：

10.1038/s41467-019-09676-y

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Approximately 30% of ER alpha breast cancer patients relapse with metastatic disease following adjuvant endocrine therapies. The connection between acquisition of drug resistance and invasive potential is poorly understood. In this study, we demonstrate that the type II keratin topological associating domain undergoes epigenetic reprogramming in aromatase inhibitors (AI)-resistant cells, leading to Keratin-80 (KRT80) upregulation. KRT80 expression is driven by de novo enhancer activation by sterol regulatory element-binding protein 1 (SREBP1). KRT80 upregulation directly promotes cytoskeletal rearrangements at the leading edge, increased focal adhesion and cellular stiffening, collectively promoting cancer cell invasion. Shearwave elasticity imaging performed on prospectively recruited patients confirms KRT80 levels correlate with stiffer tumors. Immunohistochemistry showed increased KRT80-positive cells at relapse and, using several clinical endpoints, KRT80 expression associates with poor survival. Collectively, our data uncover an unpredicted and potentially targetable direct link between epigenetic and cytoskeletal reprogramming promoting cell invasion in response to chronic AI treatment.

引用

页数：15

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