Affiliations of authors: Department of Medical Oncology (PVDG, EVDW), Department of Pathology (PVDG, AB, PVDZ, PJVD), Department of Clinical Genetics (FHM), Department of Gynecology and Obstetrics (RHMV), VU University Medical Center, Amsterdam, The Netherlands; Department of Pathology, Gerhard Domagk University, Muenster, Germany (HB).
Correspondence to: Paul J. van Diest, MD, PhD, Department of Pathology, University Medical Center, P.O. Box 85500, NL 3508 GA, Utrecht, The Netherlands (e-mail: p.j.vandiest{at}lab.azu.nl)
Foulkes et al. (1) reported that the expression of cytokeratin 5/6, indicating a basal epithelial phenotype, was statistically significantly associated with germline BRCA1 mutations in estrogen receptor (ER)- and erbB2-negative invasive breast cancers. It has recently been shown that the epidermal growth factor receptor (EGFR) is often expressed in basal-type ("stem") cells of the breast (2), extending the phenotype of basal cells to ER/erbB2/EGFR+ breast cells. We examined the expression of EGFR by immunohistochemistry in the invasive breast cancers from 21 proven carriers of BRCA1 germline mutations and five proven carriers of BRCA2 germline mutations, as well as from a control group of 430 invasive breast cancers from patients unselected for a family history of breast cancer. Only clear membrane staining for EGFR was considered as overexpression. Of the 21 BRCA1-related breast cancers, 14 (67%) showed EGFR overexpression, 19 (90%) were ER negative, and 17 (81%) were erbB2 negative. Eleven (52%) of 21 tumors were ER/erbB2/EGFR+.
All five (100%) breast cancers in BRCA2 mutation carriers showed EGFR overexpression, four (80%) were ER negative, and three (75%) of four were erbB2 negative (one could not be characterized). Two (50%) of four tumors were ER/erbB2/EGFR+. In the control group of 430 tumors, EGFR overexpression was found in only 70 (16%), and only 28 (7%) of 422 tumors were ER/erbB2/EGFR+. (Eight tumors could not be characterized for both proteins.) EGFR overexpression was statistically significantly higher in breast cancers in BRCA1 (P<.001, two-sided Fishers exact test) and BRCA2 (P<.001) mutation carriers than in the control tumors. Also, the full ER/erbB2/EGFR+ phenotype was statistically significantly more frequent in BRCA1/2 mutation carriers (P<.001).
The high frequency of EGFR overexpression fits with the poor prognosis for patients with hereditary breast cancer, but the underlying mechanism is yet unclear. Amplification of EGFR seems to be very rare in invasive breast cancer (Buerger H, unpublished data). Further, by comparative genomic hybridization, amplification at the EGFR locus was not observed (3). Genetic alterations in an expression-regulating CA repeat in the first intron of the EGFR gene (4) have not yet been studied in hereditary breast cancer. In two gene expression studies in hereditary breast cancer (5,6), increased EGFR mRNA expression was not observed, indicating that EGFR expression is probably largely posttranscriptionally regulated.
We conclude that invasive breast carcinomas in patients with a BRCA1 or BRCA2 germline mutation show a high frequency of EGFR overexpression, compatible with the previously (7) established predominantly basal phenotype (ER/erbB2) of these cancers and their aggressive clinical behavior. Thus, we urge further investigation into the mechanisms of EGFR overexpression and into new preventive strategies through EGFR targeting.
NOTES
This research was supported in part by the unrestricted Aegon International Scholarship in Oncology.
REFERENCES
1 Foulkes WD, Stefansson IM, Chappuis PO, Begin LR, Goffin JR, Wong N, et al. Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J Natl Cancer Inst 2003;95:14825.
2 DiRenzo J, Signoretti S, Nakamura N, Rivera-Gonzalez R, Sellers W, Loda M, et al. Growth factor requirements and basal phenotype of an immortalized mammary epithelial cell line. Cancer Res 2002;62:8998.
3 Wessels LF, Van Welsem T, Hart AA, vant Veer LJ, Reinders MJ, Nederlof PM. Molecular classification of breast carcinomas by comparative genomic hybridization: a specific somatic genetic profile for BRCA1 tumors. Cancer Res 2002;62:711017
4 Buerger H, Gebhardt F, Schmidt H, Beckmann A, Hutmacher K, Simon R, et al. Length and loss of heterozygosity of an intron 1 polymorphic sequence of egfr is related to cytogenetic alterations and epithelial growth factor receptor expression. Cancer Res 2000;60:8547
5 Vant Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 2002;415:5306[CrossRef][ISI][Medline]
6 Hedenfalk I, Ringner M, Ben-Dor A, Yakhini Z, Chen Y, Chebil G, et al. Molecular classification of familial non-BRCA1/BRCA2 breast cancer. Proc Natl Acad Sci U S A 2003;100:25327.
7 Korsching E, Korsching E, Packeisen J, Agelopoulos K, Eisenacher M, Voss R, et al. Cytogenetic alterations and cytokeratin expression patterns in breast cancer: integrating a new model of breast differentiation into cytogenetic pathways of breast carcinogenesis. Lab Invest 2002;82:152533.[ISI][Medline]
Correspondence about this Article
![]() |
||||
|
Oxford University Press Privacy Policy and Legal Statement |