title: Breast cancer cells respond differently to docetaxel depending on their phenotype and on survivin upregulation.
abstract: Breast cancer is characterized by molecular heterogeneity, and four major breast cancer subtypes have been identified, each characterized by significant differences in survival, prognosis, and response to therapy. We have studied the effects of docetaxel treatment on apoptosis and survivin expression in four breast cancer cell lines: MCF7 (luminal A: estrogen receptor-positive and progesterone receptor-positive, ErbB2-negative), BT474 (luminal B: estrogen receptor/progesterone receptor/ErbB2-positive), SKBR3 (HER2-like: estrogen receptor/progesterone receptor-negative, ErbB2-positive), and MDA-MB231 (basal-like: estrogen receptor/progesterone receptor/ErbB2-negative). We demonstrated that docetaxel-induced apoptosis and survivin upregulation (MCF7 p = 0.002, BT474 p = 0.001, SKBR3 p = 0.001) in luminal A/B and HER2-like cells, while it induced mainly necrosis and a lower rate of survivin upregulation (MDA-MB231 p = 0.035) in basal-like cells. Wortmannin, a p-Akt inhibitor, was able to revert surviving upregulation and, at the same time, induced an increase of docetaxel-dependent apoptosis, suggesting that reduced levels of survivin can sensitize tumor cells to apoptosis. These data show that the analyzed breast cancer cell lines respond differently to docetaxel, depending on their receptor expression profile and molecular phenotype. Yet, these data confirm that one of the pathways involved in taxane-related chemoresistance is the upregulation of survivin. Further studies on the molecular mechanisms of chemoresistance and on the different modalities of apoptosis induced by chemotherapeutic agents are requested to better understand how cancer cells evade cell death, in order to design new kind of anticancer agents and survivin could represent a future target for this kind of research.
authors.affiliation: Experimental Medicine Department, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: De Iuliis
authors.affiliation: Experimental Medicine Department, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Salerno
authors.affiliation: Experimental Medicine Department, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Giuffrida
authors.affiliation: Molecular Medicine Department, Sapienza University of Rome, 00161, Rome, Italy.
authors.forename: Bernardina
authors.initials: B
authors.lastname: Milana
authors.affiliation: Experimental Medicine Department, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy.
authors.forename: Ludovica
authors.initials: L
authors.lastname: Taglieri
authors.affiliation: Molecular Medicine Department, Sapienza University of Rome, 00161, Rome, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Rubinacci
authors.affiliation: Molecular Medicine Department, Sapienza University of Rome, 00161, Rome, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Giantulli
authors.affiliation: Molecular Medicine Department, Sapienza University of Rome, 00161, Rome, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Terella
authors.affiliation: Molecular Medicine Department, Sapienza University of Rome, 00161, Rome, Italy.
authors.forename: Ida
authors.initials: I
authors.lastname: Silvestri
authors.affiliation: Experimental Medicine Department, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy. susanna.scarpa@uniroma1.it.
authors.forename: Susanna
authors.initials: S
authors.lastname: Scarpa
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D001952:Bridged-Ring Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics*; D061986:MCF-7 Cells; D010641:Phenotype; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D011960:Receptors, Estrogen / Q000235:genetics; D011980:Receptors, Progesterone / Q000235:genetics; D000077022:Survivin; D043823:Taxoids / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D000077143:Docetaxel; D051034:Inhibitor of Apoptosis Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D000077022:Survivin; D043823:Taxoids; C107489:BIRC5 protein, human; C080625:taxane
keywords: Apoptosis; Breast cancer; Chemoresistance; Docetaxel; Survivin; Wortmannin