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: Francesca De Iuliis, Gerardo Salerno, Anna Giuffrida, Bernardina Milana, Ludovica Taglieri, Giovanna Rubinacci, Sabrina Giantulli, Federica Terella, Ida Silvestri, Susanna Scarpa
• Journal: Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine (Tumour Biol) Vol. 37 Issue 2 Pg. 2603-11 (Feb 2016) ISSN: 1423-0380 [Electronic] Netherlands
• PMID: 26392111 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• BIRC5 protein, human
• Bridged-Ring Compounds
• Inhibitor of Apoptosis Proteins
• Receptors, Estrogen
• Receptors, Progesterone
• Survivin
• Taxoids
• Docetaxel
• taxane
• Receptor, ErbB-2

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects, genetics)
• Breast Neoplasms (drug therapy, genetics)
• Bridged-Ring Compounds (pharmacology)
• Cell Line, Tumor
• Docetaxel
• Drug Resistance, Neoplasm (genetics)
• Gene Expression (drug effects, genetics)
• Gene Expression Regulation, Neoplastic (drug effects, genetics)
• Humans
• Inhibitor of Apoptosis Proteins (genetics)
• MCF-7 Cells
• Phenotype
• Receptor, ErbB-2 (genetics)
• Receptors, Estrogen (genetics)
• Receptors, Progesterone (genetics)
• Survivin
• Taxoids (pharmacology)
• Up-Regulation (drug effects, genetics)