Fulvestrant treatment alters MDM2 protein turnover and sensitivity of human breast carcinoma cells to chemotherapeutic drugs

Sonia C Dolfi; Adriana V Jäger; Daniel J Medina; Bruce G Haffty; Jin-Ming Yang; Kim M Hirshfield

doi:10.1016/j.canlet.2014.04.009

Fulvestrant treatment alters MDM2 protein turnover and sensitivity of human breast carcinoma cells to chemotherapeutic drugs

Cancer Lett. 2014 Aug 1;350(1-2):52-60. doi: 10.1016/j.canlet.2014.04.009. Epub 2014 Apr 18.

Authors

Sonia C Dolfi¹, Adriana V Jäger², Daniel J Medina¹, Bruce G Haffty³, Jin-Ming Yang⁴, Kim M Hirshfield⁵

Affiliations

¹ Department of Medicine, Rutgers Cancer Institute of New Jersey, Rutgers The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, United States.
² Instituto de Investigaciones en Ingeniería Genética y Biología Molecular (INGEBI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
³ Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, United States.
⁴ Department of Pharmacology, The Penn State Cancer Institute, Pennsylvania State University College of Medicine, and Milton S. Hershey Medical Center, 500 University Drive, Hershey, PA 17033, United States.
⁵ Department of Medicine, Rutgers Cancer Institute of New Jersey, Rutgers The State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, United States. Electronic address: hirshfie@cinj.rutgers.edu.

Abstract

The human homologue of mouse double minute 2 (MDM2) is overexpressed in tumors and contributes to tumorigenesis through inhibition of p53 activity. We investigated the effect of the anti-estrogen fulvestrant on MDM2 expression and sensitivity of estrogen receptor positive human breast cancer cell lines to chemotherapeutics. Fulvestrant down-regulated MDM2 through increased protein turnover. Fulvestrant blocked estrogen-dependent up-regulation of MDM2 and decreased basal expression of MDM2 in the absence of estradiol. As combinations of fulvestrant with doxorubicin, etoposide or paclitaxel were synergistic, altering cell cycle distribution and increasing cell death, this provides rationale for testing combinatorial chemotherapy with fulvestrant as a novel therapeutic strategy for patients with advanced breast cancer.

Keywords: Breast cancer; Chemotherapy; Estrogen receptor; Fulvestrant; MDM2.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Antineoplastic Agents, Hormonal / therapeutic use*
Apoptosis / drug effects
Breast Neoplasms / drug therapy*
Cell Cycle / genetics
Cell Line, Tumor
Cellular Senescence / drug effects
Cyclin-Dependent Kinase Inhibitor p21 / biosynthesis
Down-Regulation / drug effects
Doxorubicin / pharmacology
Drug Resistance, Neoplasm / drug effects*
Estradiol / analogs & derivatives*
Estradiol / therapeutic use
Estrogen Antagonists / therapeutic use*
Etoposide / pharmacology
Female
Fulvestrant
Humans
MCF-7 Cells
Paclitaxel / pharmacology
Proto-Oncogene Proteins c-mdm2 / biosynthesis
Proto-Oncogene Proteins c-mdm2 / genetics
Proto-Oncogene Proteins c-mdm2 / metabolism*
RNA, Messenger / biosynthesis
Receptors, Estrogen / antagonists & inhibitors*
Tumor Suppressor Protein p53 / biosynthesis

Substances

Antineoplastic Agents, Hormonal
Cyclin-Dependent Kinase Inhibitor p21
Estrogen Antagonists
RNA, Messenger
Receptors, Estrogen
Tumor Suppressor Protein p53
Fulvestrant
Estradiol
Etoposide
Doxorubicin
MDM2 protein, human
Proto-Oncogene Proteins c-mdm2
Paclitaxel

Grants and funding

P30 CA072720/CA/NCI NIH HHS/United States