Inhibition of HER1 signaling pathway enhances antitumor effect of endocrine therapy in breast cancer.
Epidermal growth factor receptor (EGFR)/HER1 is expressed at high levels in at least 20% of breast cancers. This high expression correlates with a poor prognosis in patients with breast cancer. Experimental and clinical findings suggest that aberrant activation of tyrosine receptor kinases, such as HER1 pathway, play a causal role in the development of antiestrogen resistance in breast cancer. Recent preclinical and clinical evidence shows that inhibition of growth factor signaling pathways suppresses the growth of malignant cells without serious toxicities. To test the hypothesis that inhibition of the HER1 signaling pathway enhances the antitumor effect of endocrine therapy, a promising signal transduction inhibitor (STI) of HER1 tyrosine kinase, gefitinib, and an estrogen receptor (ER) antagonist, fulvestrant, were administered to human breast cancer cells. Our experimental results have revealed that gefitinib additively enhances the antitumor effect of fulvestrant in estrogen receptor (ER)-positive breast cancer cells under estrogen-supplemented conditions. An additive increase in the protein expression level of a cyclin-dependent kinase inhibitor, p21 may play a key role of this additive cytostatic effect. The rationale and future perspectives of the combined use of STIs with endocrine therapy in breast cancer are discussed.
Kurebayashi
Junichi
J
Department of Breast and Thyroid Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan.
Okubo
Sumiko
S
Yamamoto
Yutaka
Y
Sonoo
Hiroshi
H
D000970:Antineoplastic Agents / Q000494:pharmacology*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000627:therapeutic use; D005260:Female; D000077267:Fulvestrant; D000077156:Gefitinib; D005786:Gene Expression Regulation / Q000235:genetics; D018773:Genes, erbB-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics
D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D020847:Estrogen Receptor Modulators; D011799:Quinazolines; D000077267:Fulvestrant; D004958:Estradiol; D004815:Epidermal Growth Factor; D000077156:Gefitinib