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

// Guilhem Bousquet 1, 2, 3, 4 , Morad El Bouchtaoui 2 , Tan Sophie 2 , Christophe Leboeuf 1, 2 , Cedric de Bazelaire 1, 2, 5 , Philippe Ratajczak 1, 2 , Sylvie Giacchetti 6 , Anne de Roquancourt 1, 2, 7 , Philippe Bertheau 1, 2, 7 , Laurence Verneuil 1, 2 , Jean-Paul Feugeas 8 , Marc Espie 1, 6 , Anne Janin 1, 2, 7 1 Universite Paris Diderot, Sorbonne Paris Cite, Laboratoire Pathologie, Paris, France 2 INSERM, Paris, France 3 Universite Paris 13, Villetaneuse, France 4 AP, HP, Avicenne, Service Oncologie, Paris, France 5 AP HP Hopital Saint-Louis, Service Radiologie, Paris, France 6 AP HP Hopital Saint-Louis, Centre Maladies Sein, Paris, France 7 AP HP Hopital Saint-Louis, Service Pathologie, Paris, France 8 INSERM, Paris, France Correspondence to: Guilhem Bousquet, email: guilhem.bousquet@aphp.fr Anne Janin, email: anne.janin1165@gmail.com 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.