Targeting autophagic cancer stem-cells to reverse chemoresistance in human triple negative breast cancer

被引：45

作者：

Bousquet, Guilhem ^{[1
,2
,3
,4
]}

El Bouchtaoui, Morad ^{[2
]}

Sophie, Tan ^{[2
]}

Leboeuf, Christophe ^{[1
,2
]}

de Bazelaire, Cedric ^{[1
,2
,5
]}

Ratajczak, Philippe ^{[1
,2
]}

Giacchetti, Sylvie ^{[6
]}

de Roquancourt, Anne ^{[1
,2
,7
]}

Bertheau, Philippe ^{[1
,2
,7
]}

Verneuil, Laurence ^{[1
,2
]}

Feugeas, Jean-Paul ^{[2
]}

Espie, Marc ^{[1
,6
]}

Janin, Anne ^{[1
,2
,7
]}

机构：

[1] Univ Paris Diderot, Sorbonne Paris Cite, Lab Pathol, Paris, France

[2] INSERM, Paris, France

[3] Univ Paris 13, Villetaneuse, France

[4] Avicenne, AP HP, Serv Oncol, Paris, France

[5] Hop St Louis, AP HP, Serv Radiol, Paris, France

[6] Hop St Louis, AP HP, Ctr Malad Sein, Paris, France

[7] Hop St Louis, AP HP, Serv Pathol, Paris, France

来源：

ONCOTARGET | 2017年 / 8卷 / 21期

关键词：

breast cancer stem cells; TNBC; chemoresistance; autophagy; hypoxia; HYPOXIA-INDUCED AUTOPHAGY; PANCREATIC-CANCER; CHEMOTHERAPY; RESISTANCE; INHIBITION; EXPRESSION; HETEROGENEITY; PACLITAXEL; SURVIVAL; HYDROXYCHLOROQUINE;

D O I：

10.18632/oncotarget.16925

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

There is growing evidence for the role of cancer stem-cells in drug resistance, but with few in situ studies on human tumor samples to decipher the mechanisms by which they resist anticancer agents. Triple negative breast cancer (TNBC) is the most severe sub-type of breast cancer, occurring in younger women and associated with poor prognosis even when treated at a localized stage. We investigated here the relationship between complete pathological response after chemotherapy and breast cancer stem-cell characteristics in pre-treatment biopsies of 78 women with triple negative breast carcinoma (TNBC). We found that chemoresistance was associated with large numbers of breast cancer stem-cells, and that these cancer stem-cells were neither proliferative nor apoptotic, but in an autophagic state related to hypoxia. Using relevant pharmacological models of patient-derived TNBC xenografts, we further investigated the role of autophagy in chemoresistance of breast cancer stem-cells. We demonstrated that hypoxia increased drug resistance of autophagic TNBC stem-cells, and showed that molecular or chemical inhibition of autophagic pathway was able to reverse chemoresistance. Our results support breast cancer stem-cell evaluation in pre-treatment biopsies of TNBC patients, and the need for further research on autophagy inhibition to reverse resistance to chemotherapy.

引用

页码：35205 / 35221

页数：17

共 54 条

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