ErbB (HER) receptors can abrogate antiestrogen action in human breast cancer by multiple signaling mechanisms.
It has been reported that overexpression of the epidermal growth factor receptor (erbB1) or its homologous receptor, HER2 (erbB2), can confer antiestrogen resistance to estrogen receptor (ER)-positive human breast cancer cells. Aberrant signaling by receptors of the erbB network up-regulates a number of signaling pathways, which include phospholipase C-gamma1, Ras-Raf-mitogen-activated protein/extracellular signal-regulated kinase kinase-mitogen-activated protein kinase, phosphatidylinositol 3'-kinase and its target, the serine/threonine kinase Akt, stress-activated protein kinases, signal transducers and activators of transcription, and c-Jun-NH(2)-terminal kinase (JNK). Akt has been reported to induce estrogen-independent transcription of ER. Here we show that transfection of ER-positive, HER2 gene-amplified BT-74 cells with an expression vector encoding dominant-negative (K179M) Akt1 partially restored the ability of tamoxifen to inhibit estradiol-stimulated ER reporter activity. Infection of MCF-7 cells with an adenovirus encoding myristoylated, constitutively active Akt induced ER reporter activity in the absence of estradiol and resulted in tamoxifen resistance of these cells in culture. Data will be presented to suggest that, in addition to mitogen-activated protein kinase, Akt is an important mediator of HER2-mediated antiestrogen resistance in human breast cancer cells.
Kurokawa
Hirokazu
H
Departments of Medicine and Cancer Biology and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6307, USA.
Arteaga
Carlos L
CL
D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000502:physiology*; D004965:Estrogen Antagonists / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D009376:Neoplasms, Hormone-Dependent; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology*; D013629:Tamoxifen / Q000627:therapeutic use*; D014162:Transfection
D018931:Antineoplastic Agents, Hormonal; D066246:ErbB Receptors; D004965:Estrogen Antagonists; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D013629:Tamoxifen; C494918:AKT1 protein, human