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

Guilhem Bousquet; Morad El Bouchtaoui; Tan Sophie; Christophe Leboeuf; Cédric de Bazelaire; Philippe Ratajczak; Sylvie Giacchetti; Anne de Roquancourt; Philippe Bertheau; Laurence Verneuil; Jean-Paul Feugeas; Marc Espié; Anne Janin

doi:10.18632/oncotarget.16925

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Research Papers:

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

Guilhem Bousquet _, Morad El Bouchtaoui, Tan Sophie, Christophe Leboeuf, Cédric de Bazelaire, Philippe Ratajczak, Sylvie Giacchetti, Anne de Roquancourt, Philippe Bertheau, Laurence Verneuil, Jean-Paul Feugeas, Marc Espié and Anne Janin

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Oncotarget. 2017; 8:35205-35221. https://doi.org/10.18632/oncotarget.16925

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Abstract

Guilhem Bousquet1,2,3,4, Morad El Bouchtaoui2, Tan Sophie2, Christophe Leboeuf1,2, Cédric de Bazelaire1,2,5, Philippe Ratajczak1,2, Sylvie Giacchetti6, Anne de Roquancourt1,2,7, Philippe Bertheau1,2,7, Laurence Verneuil1,2, Jean-Paul Feugeas8, Marc Espié1,6, Anne Janin1,2,7

1Université Paris Diderot, Sorbonne Paris Cité, Laboratoire Pathologie, Paris, France

2INSERM, Paris, France

3Université Paris 13, Villetaneuse, France

4AP, HP, Avicenne, Service Oncologie, Paris, France

5AP HP Hôpital Saint-Louis, Service Radiologie, Paris, France

6AP HP Hôpital Saint-Louis, Centre Maladies Sein, Paris, France

7AP HP Hôpital Saint-Louis, Service Pathologie, Paris, France

8INSERM, Paris, France

Correspondence to:

Guilhem Bousquet, email: [email protected]

Anne Janin, email: [email protected]

Keywords: breast cancer stem cells, TNBC, chemoresistance, autophagy, hypoxia

Received: March 21, 2017 Accepted: March 29, 2017 Published: April 07, 2017

ABSTRACT

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.

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Research Papers:

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

Abstract