EGFRvIII-induced estrogen-independence, tamoxifen-resistance phenotype correlates with PgR expression and modulation of apoptotic molecules in breast cancer.
The tumor-specific, ligand-independent, constitutively active epidermal growth factor receptor (EGFR) variant, EGFRvIII, remains understudied in breast cancer. Here, we report that expression of EGFRvIII in the ErbB-2-overexpressing, estrogen-dependent MDA-MB-361 breast cancer cell line resulted in significant estrogen-independent tumor growth in ovariectomized, athymic nude mice in comparison to MDA-MB-361/wt cells. MDA-MB-361/vIII breast cancer cells maintained estrogen-induced tumor growth, but were tamoxifen-resistant in the presence of estrogen, while MDA-MB-361/wt cells had a significant reduction in tumor growth in the presence of estrogen and tamoxifen. Tamoxifen alone did not have a significant effect on EGFRvIII-mediated estrogen-independent tumor growth. Constitutive signaling from the EGFRvIII receptor resulted in an increased activation of both the Akt and MAPK pathways. Compared to estrogen-dependent, tamoxifen-sensitive MCF-7/vIII breast cancer cells, which had unchanged levels of ERalpha, but an increase in progesterone receptor (PgR) in comparison to MCF-7/wt cells, MDA-MB-361/vIII cells had a reduction in ERalpha expression as well as a more pronounced reduction in PgR compared with MDA-MB-361/wt cells. EGFRvIII expression was also significantly associated with an absence of PgR protein in invasive human breast cancer specimens. Alterations of proapoptotic proteins and antiapoptotic proteins were observed in EGFRvIII transfectants. In conclusion, constitutive signaling through EGFRvIII and its downstream effector proteins crosstalks with the ERalpha pathway, resulting in loss of PgR expression and alterations in the apoptotic pathway, which may result in the estrogen-independent, tamoxifen-resistant phenotype conferred to EGFRvIII-expressing breast cancer cells.
Zhang
Yang
Y
Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University Medical Center, Washington, DC, USA.
Su
Hua
H
Rahimi
Massod
M
Tochihara
Ryan
R
Tang
Careen
C
D000818:Animals; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000032:analysis; D004967:Estrogens / Q000502:physiology; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis*; D011980:Receptors, Progesterone / Q000032:analysis*; D013629:Tamoxifen / Q000494:pharmacology*; D051020:bcl-X Protein / Q000032:analysis*
D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D004967:Estrogens; D019253:Proto-Oncogene Proteins c-bcl-2; D011980:Receptors, Progesterone; D051020:bcl-X Protein; C410723:epidermal growth factor receptor VIII; D013629:Tamoxifen; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt