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


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.


CONCLUSIONS
ER-HER co-targeting enhanced the antitumor effects and can bring about effects of targeting HER2 in models of HER2-normal breast cancer.
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.
Ashok K
AK
Chakraborty
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.
Ranee
R
Mehra
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.
Michael P
MP
Digiovanna
D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004965:Estrogen Antagonists / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis / Q000037:antagonists & inhibitors*; D011960:Receptors, Estrogen / Q000032:analysis; D013629:Tamoxifen / Q000008:administration & dosage; D000068878:Trastuzumab
D061067:Antibodies, Monoclonal, Humanized; D004965:Estrogen Antagonists; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D013629:Tamoxifen; D000068878:Trastuzumab; C508053:ERBB2 protein, human
Breast cancer; EGFR; GW2974; HER2; apoptosis; estrogen receptor (ER); fulvestrant (Faslodex); proliferation; tamoxifen; trastuzumab (Herceptin)