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Anticancer Res. 2015 Mar;35(3):1243-50.

Co-targeting ER and HER family receptors induces apoptosis in HER2-normal or overexpressing breast cancer models.

Author information

1
Departments of Internal Medicine (Section of Medical Oncology) and Pharmacology, and the Yale Cancer Center/Smilow Cancer Hospital, Yale University School of Medicine, New Haven, CT, U.S.A.
2
Departments of Internal Medicine (Section of Medical Oncology) and Pharmacology, and the Yale Cancer Center/Smilow Cancer Hospital, Yale University School of Medicine, New Haven, CT, U.S.A. michael.digiovanna@yale.edu.

Abstract

BACKGROUND:

Estrogen receptor (ER) and human epidermal growth factor receptor (HER) family receptors interact in breast cancer; co-targeting these receptors is of interest. We previously reported on a synergistic growth inhibition for the combination of trastuzumab plus tamoxifen in HER2+/ER+ BT474 cells, but no induction of apoptosis. Herein we describe the effects of co-targeting in models of differing HER2 overexpression status (MCF7 HER2-normal/ER+, BT474 HER2-overexpressing/ER+).

MATERIALS AND METHODS:

Assays of proliferation were carried-out using WST-1, cell cycle using flow cytometry, and apoptosis by determination of sub-G1 population and by annexin-V.

RESULTS:

Combining a dual HER2/EGFR kinase inhibitor with anti-estrogens induces apoptosis of BT474 cells. Furthermore, in MCF7 cells, despite HER2-normal status and lack of response to single-agent HER2 inhibitors, addition of HER2 inhibitors or dual HER2/EGFR inhibitor to anti-estrogens augments the antiproliferative effect of anti-estrogens, and converts the drug effect from cytostatic to apoptosis-inducing.

CONCLUSION:

ER-HER co-targeting enhanced the antitumor effects and can bring about effects of targeting HER2 in models of HER2-normal breast cancer.

KEYWORDS:

Breast cancer; EGFR; GW2974; HER2; apoptosis; estrogen receptor (ER); fulvestrant (Faslodex); proliferation; tamoxifen; trastuzumab (Herceptin)

PMID:
25750271
[Indexed for MEDLINE]

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