Survivin family proteins as novel molecular determinants of doxorubicin resistance in organotypic human breast tumors

Alice Faversani, Valentina Vaira, Giacomina P. Moro, Delfina Tosi, Alessia Lopergolo, David C. Schultz, Dayana Rivadeneira, Dario C. Altieri, Silvano Bosari

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Introduction: The molecular determinants of breast cancer resistance to first-line anthracycline-containing chemotherapy are unknown.Methods: We examined the response to doxorubicin of organotypic cultures of primary human breast tumors ex vivo with respect to cell proliferation, DNA damage and modulation of apoptosis. Samples were analyzed for genome-wide modulation of cell death pathways, differential activation of p53, and the role of survivin family molecules in drug resistance. Rational drug combination regimens were explored by high-throughput screening, and validated in model breast cancer cell types.Results: Doxorubicin treatment segregated organotypic human breast tumors into distinct Responder or Non Responder groups, characterized by differential proliferative index, stabilization of p53, and induction of apoptosis. Conversely, tumor histotype, hormone receptor or human epidermal growth factor receptor-2 (HER2) status did not influence chemotherapy sensitivity. Global analysis of cell death pathways identified survivin and its alternatively spliced form, survivin-ΔEx3 as uniquely overexpressed in Non Responder breast tumors. Forced expression of survivin-ΔEx3 preserved cell viability and prevented doxorubicin-induced apoptosis in breast cancer cell types. High-throughput pharmacologic targeting of survivin family proteins with a small-molecule survivin suppressant currently in the clinic (YM155) selectively potentiated the effect of doxorubicin, but not other chemotherapeutics in breast cancer cell types, and induced tumor cell apoptosis.Conclusions: Survivin family proteins are novel effectors of doxorubicin resistance in chemotherapy-naive breast cancer. The incorporation of survivin antagonist(s) in anthracycline-containing regimens may have improved clinical activity in these patients.

Original languageEnglish
Article numberR55
JournalBreast Cancer Research
Volume16
Issue number3
DOIs
Publication statusPublished - May 30 2014

Fingerprint

Doxorubicin
Breast Neoplasms
Proteins
Apoptosis
Anthracyclines
Drug Therapy
Cell Death
Drug Combinations
Drug Resistance
DNA Damage
Neoplasms
Cell Survival
Cell Proliferation
Genome
Hormones

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Survivin family proteins as novel molecular determinants of doxorubicin resistance in organotypic human breast tumors. / Faversani, Alice; Vaira, Valentina; Moro, Giacomina P.; Tosi, Delfina; Lopergolo, Alessia; Schultz, David C.; Rivadeneira, Dayana; Altieri, Dario C.; Bosari, Silvano.

In: Breast Cancer Research, Vol. 16, No. 3, R55, 30.05.2014.

Research output: Contribution to journalArticle

Faversani, Alice ; Vaira, Valentina ; Moro, Giacomina P. ; Tosi, Delfina ; Lopergolo, Alessia ; Schultz, David C. ; Rivadeneira, Dayana ; Altieri, Dario C. ; Bosari, Silvano. / Survivin family proteins as novel molecular determinants of doxorubicin resistance in organotypic human breast tumors. In: Breast Cancer Research. 2014 ; Vol. 16, No. 3.
@article{03fcb449a2184db5882a720b61aeeced,
title = "Survivin family proteins as novel molecular determinants of doxorubicin resistance in organotypic human breast tumors",
abstract = "Introduction: The molecular determinants of breast cancer resistance to first-line anthracycline-containing chemotherapy are unknown.Methods: We examined the response to doxorubicin of organotypic cultures of primary human breast tumors ex vivo with respect to cell proliferation, DNA damage and modulation of apoptosis. Samples were analyzed for genome-wide modulation of cell death pathways, differential activation of p53, and the role of survivin family molecules in drug resistance. Rational drug combination regimens were explored by high-throughput screening, and validated in model breast cancer cell types.Results: Doxorubicin treatment segregated organotypic human breast tumors into distinct Responder or Non Responder groups, characterized by differential proliferative index, stabilization of p53, and induction of apoptosis. Conversely, tumor histotype, hormone receptor or human epidermal growth factor receptor-2 (HER2) status did not influence chemotherapy sensitivity. Global analysis of cell death pathways identified survivin and its alternatively spliced form, survivin-ΔEx3 as uniquely overexpressed in Non Responder breast tumors. Forced expression of survivin-ΔEx3 preserved cell viability and prevented doxorubicin-induced apoptosis in breast cancer cell types. High-throughput pharmacologic targeting of survivin family proteins with a small-molecule survivin suppressant currently in the clinic (YM155) selectively potentiated the effect of doxorubicin, but not other chemotherapeutics in breast cancer cell types, and induced tumor cell apoptosis.Conclusions: Survivin family proteins are novel effectors of doxorubicin resistance in chemotherapy-naive breast cancer. The incorporation of survivin antagonist(s) in anthracycline-containing regimens may have improved clinical activity in these patients.",
author = "Alice Faversani and Valentina Vaira and Moro, {Giacomina P.} and Delfina Tosi and Alessia Lopergolo and Schultz, {David C.} and Dayana Rivadeneira and Altieri, {Dario C.} and Silvano Bosari",
year = "2014",
month = "5",
day = "30",
doi = "10.1186/bcr3666",
language = "English",
volume = "16",
journal = "Breast Cancer Research",
issn = "1465-5411",
publisher = "BioMed Central",
number = "3",

}

TY - JOUR

T1 - Survivin family proteins as novel molecular determinants of doxorubicin resistance in organotypic human breast tumors

AU - Faversani, Alice

AU - Vaira, Valentina

AU - Moro, Giacomina P.

AU - Tosi, Delfina

AU - Lopergolo, Alessia

AU - Schultz, David C.

AU - Rivadeneira, Dayana

AU - Altieri, Dario C.

AU - Bosari, Silvano

PY - 2014/5/30

Y1 - 2014/5/30

N2 - Introduction: The molecular determinants of breast cancer resistance to first-line anthracycline-containing chemotherapy are unknown.Methods: We examined the response to doxorubicin of organotypic cultures of primary human breast tumors ex vivo with respect to cell proliferation, DNA damage and modulation of apoptosis. Samples were analyzed for genome-wide modulation of cell death pathways, differential activation of p53, and the role of survivin family molecules in drug resistance. Rational drug combination regimens were explored by high-throughput screening, and validated in model breast cancer cell types.Results: Doxorubicin treatment segregated organotypic human breast tumors into distinct Responder or Non Responder groups, characterized by differential proliferative index, stabilization of p53, and induction of apoptosis. Conversely, tumor histotype, hormone receptor or human epidermal growth factor receptor-2 (HER2) status did not influence chemotherapy sensitivity. Global analysis of cell death pathways identified survivin and its alternatively spliced form, survivin-ΔEx3 as uniquely overexpressed in Non Responder breast tumors. Forced expression of survivin-ΔEx3 preserved cell viability and prevented doxorubicin-induced apoptosis in breast cancer cell types. High-throughput pharmacologic targeting of survivin family proteins with a small-molecule survivin suppressant currently in the clinic (YM155) selectively potentiated the effect of doxorubicin, but not other chemotherapeutics in breast cancer cell types, and induced tumor cell apoptosis.Conclusions: Survivin family proteins are novel effectors of doxorubicin resistance in chemotherapy-naive breast cancer. The incorporation of survivin antagonist(s) in anthracycline-containing regimens may have improved clinical activity in these patients.

AB - Introduction: The molecular determinants of breast cancer resistance to first-line anthracycline-containing chemotherapy are unknown.Methods: We examined the response to doxorubicin of organotypic cultures of primary human breast tumors ex vivo with respect to cell proliferation, DNA damage and modulation of apoptosis. Samples were analyzed for genome-wide modulation of cell death pathways, differential activation of p53, and the role of survivin family molecules in drug resistance. Rational drug combination regimens were explored by high-throughput screening, and validated in model breast cancer cell types.Results: Doxorubicin treatment segregated organotypic human breast tumors into distinct Responder or Non Responder groups, characterized by differential proliferative index, stabilization of p53, and induction of apoptosis. Conversely, tumor histotype, hormone receptor or human epidermal growth factor receptor-2 (HER2) status did not influence chemotherapy sensitivity. Global analysis of cell death pathways identified survivin and its alternatively spliced form, survivin-ΔEx3 as uniquely overexpressed in Non Responder breast tumors. Forced expression of survivin-ΔEx3 preserved cell viability and prevented doxorubicin-induced apoptosis in breast cancer cell types. High-throughput pharmacologic targeting of survivin family proteins with a small-molecule survivin suppressant currently in the clinic (YM155) selectively potentiated the effect of doxorubicin, but not other chemotherapeutics in breast cancer cell types, and induced tumor cell apoptosis.Conclusions: Survivin family proteins are novel effectors of doxorubicin resistance in chemotherapy-naive breast cancer. The incorporation of survivin antagonist(s) in anthracycline-containing regimens may have improved clinical activity in these patients.

UR - http://www.scopus.com/inward/record.url?scp=84902536479&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84902536479&partnerID=8YFLogxK

U2 - 10.1186/bcr3666

DO - 10.1186/bcr3666

M3 - Article

C2 - 24886669

AN - SCOPUS:84902536479

VL - 16

JO - Breast Cancer Research

JF - Breast Cancer Research

SN - 1465-5411

IS - 3

M1 - R55

ER -