Overexpression of the glucose-regulated stress gene GRP78 in malignant but not benign human breast lesions

Patricia M. Fernandez, Sana O. Tabbara, Lisa Jacobs, Frank C R Manning, Theodore N. Tsangaris, Arnold M. Schwartz, Katherine A. Kennedy, Steven R. Patierno

Research output: Contribution to journalArticle

Abstract

The 78 kDa glucose-regulated stress protein GRP78 is induced by physiological stress conditions such as hypoxia, low pH, and glucose deprivation which often exist in the microenvironments of solid tumors. Activation of this stress pathway occurs in response to several pro-apoptotic stimuli. In vitro studies have demonstrated a correlation between induced expression of GRP78 and resistance to apoptotic death induced by topoisomerase II-directed drugs. We were interested in characterizing this protein in human breast lesions for potential implications in chemotherapeutic intervention. Surgical specimens of human breast lesions and paired normal tissues from the same patients were flash frozen for these studies. Total RNA and/or protein were extracted from these tissues and used in northern and/or western blot analyses, respectively, to quantify the relative expression of GRP78. Northern blot analysis indicated that 0/5 benign breast lesions, 3/5 estrogen receptor positive (ER+) breast tumors, and 6/9 estrogen receptor negative (ER-) breast tumors exhibited overexpression of GRP78 mRNA compared to paired normal tissues, with fold overexpressions ranging from 1.8 to 20. Western blot analyses correlated with these findings since 0/5 benign breast lesions, 4/6 ER+ breast tumors, and 3/3 ER- breast tumors overexpressed GRP78 protein with fold overexpressions ranging from 1.8 to 19. Immunohistochemical analysis of these tissues demonstrated that the expression of GRP78 was heterogeneous among the cells comprising different normal and malignant glands, but confirmed the overexpression of GRP78 in most of the more aggressive ER- tumors. These results suggest that some breast tumors exhibit adverse microenvironment conditions that induce the overexpression of specific stress genes that may play a role in resistance to apoptosis and decreased chemotherapeutic efficacy.

Original languageEnglish (US)
Pages (from-to)15-26
Number of pages12
JournalBreast Cancer Research and Treatment
Volume59
Issue number1
DOIs
StatePublished - 2000
Externally publishedYes

Fingerprint

Breast
Estrogen Receptors
Breast Neoplasms
Glucose
Genes
Northern Blotting
Western Blotting
Type II DNA Topoisomerase
Physiological Stress
Proteins
Tumor Microenvironment
Heat-Shock Proteins
RNA
Apoptosis
Messenger RNA
Pharmaceutical Preparations
Neoplasms

Keywords

  • Chemoresistance
  • Endoplasmic reticulum
  • GRP78
  • Human breast cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Fernandez, P. M., Tabbara, S. O., Jacobs, L., Manning, F. C. R., Tsangaris, T. N., Schwartz, A. M., ... Patierno, S. R. (2000). Overexpression of the glucose-regulated stress gene GRP78 in malignant but not benign human breast lesions. Breast Cancer Research and Treatment, 59(1), 15-26. https://doi.org/10.1023/A:1006332011207

Overexpression of the glucose-regulated stress gene GRP78 in malignant but not benign human breast lesions. / Fernandez, Patricia M.; Tabbara, Sana O.; Jacobs, Lisa; Manning, Frank C R; Tsangaris, Theodore N.; Schwartz, Arnold M.; Kennedy, Katherine A.; Patierno, Steven R.

In: Breast Cancer Research and Treatment, Vol. 59, No. 1, 2000, p. 15-26.

Research output: Contribution to journalArticle

Fernandez, PM, Tabbara, SO, Jacobs, L, Manning, FCR, Tsangaris, TN, Schwartz, AM, Kennedy, KA & Patierno, SR 2000, 'Overexpression of the glucose-regulated stress gene GRP78 in malignant but not benign human breast lesions', Breast Cancer Research and Treatment, vol. 59, no. 1, pp. 15-26. https://doi.org/10.1023/A:1006332011207
Fernandez, Patricia M. ; Tabbara, Sana O. ; Jacobs, Lisa ; Manning, Frank C R ; Tsangaris, Theodore N. ; Schwartz, Arnold M. ; Kennedy, Katherine A. ; Patierno, Steven R. / Overexpression of the glucose-regulated stress gene GRP78 in malignant but not benign human breast lesions. In: Breast Cancer Research and Treatment. 2000 ; Vol. 59, No. 1. pp. 15-26.
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