Detection of Epstein-Barr Virus in Rapidly Growing Fibroadenomas of the Breast in Immunosuppressed Hosts

Abstract

Fibroadenomas are the most common benign tumors of the female breast and are associated with a slight increase in the risk of subsequent breast cancer. Multiple fibroadenomas have been described in patients after renal transplantation and are thought to be secondary to drug-related growth stimulation. Epstein-Barr virus (EBV) has been detected in many neoplasms, including breast cancer. We set out to investigate whether EBV plays a role in the development of rapidly growing fibroadenomas in immunocompromised patients. We studied 19 fibroadenomas and one invasive ductal carcinoma that developed after organ transplantation or treatment for lupus erythematosus. As a control group we included 11 fibroadenomas from non-immunocompromised patients. DNA was amplified using polymerase chain reaction (PCR) of the EBV-encoded small RNA (EBER-2) DNA sequence. EBV latent membrane protein 1 (LMP-1) transcripts were amplified using reverse transcription (RT) PCR. Immunohistochemical (IHC) staining for LMP-1 protein was performed. A total of 9 out of 20 tumors (45%) were concordantly positive by PCR and IHC. IHC stained exclusively the epithelial cells. All the fibroadenomas in non-immunocompromised patients were negative for LMP-1 (Fisher's exact test P ‫؍‬ .0006). These data suggest that EBV is associated with fibroadenomas in this immunosuppressed population and that the infection is specifically localized to epithelial cells. This is the first study suggesting a role for EBV in the pathogenesis of fibroadenomas.

Epstein–Barr virus gene expression in human breast cancer: protagonist or passenger?

“…The herpesvirus EBV, a causative agent for infectious mononucleosis, has been associated with various malignancies with frequencies that vary from 100% (in poorly differentiated NPC) to a few percent only (in adenocarcinomas) (IARC, 1997), or, as recently discussed, up to 45% (nine out of 20) in fibroadenomas from HIV-positive individuals (Kleer et al, 2002). In some studies, EBV has been identified as a component of breast cancers (Labrecque et al, 1995;Luqmani and Shousha, 1995;Bonnet et al, 1999;Fina et al, 2001;Grinstein et al, 2002;Kleer et al, 2002) in up to 50% of cases examined (Bonnet et al, 1999).…”

“…In some studies, EBV has been identified as a component of breast cancers (Labrecque et al, 1995;Luqmani and Shousha, 1995;Bonnet et al, 1999;Fina et al, 2001;Grinstein et al, 2002;Kleer et al, 2002) in up to 50% of cases examined (Bonnet et al, 1999). Interestingly, whereas association of EBV with about 10% of human gastric carcinomas (Shibata and Weiss, 1992;Rowlands et al, 1993;Galetsky et al, 1997;Takano et al, 1999;Yoshiyama et al, 1997;Zur Hausen et al, 2000) is accepted as real and meaningful, the association of this virus with human breast cancer Figure 2 Analysis of expression of EBV RNA in viral DNA-positive breast cancer biopsies (BCs 1, 4, 10 -13).…”

“…Late exposure to a common virus, such as human cytomegalovirus, has been suggested as a risk factor for breast carcinomas (Richardson, 1997), and Yasui et al (2001) argue that delayed infection with Epstein -Barr virus (EBV) may also be a risk for this malignancy. For EBV, there is evidence for its presence and expression in subpopulations (up to 50%, but frequently less) of breast tumours (Labrecque et al, 1995;Luqmani and Shousha, 1995;Bonnet et al, 1999;Joab, 2000;Fina et al, 2001;Grinstein et al, 2002;Kleer et al, 2002; see the discussion by Magrath and Bhatia, 1999). Data that illustrate direct entry of this virus into epithelial cells by routes involving an epithelial-specific receptor (Sixbey et al, 1987;Yoshiyama et al, 1997) or cell -cell contact with infected lymphocytes (Bayliss and Wolf, 1980;Speck and Longnecker, 2000) have been put forward.…”

Benign Breast Diseases: Classification, Diagnosis, and Management

“…A direct association has been noted between oral contraceptive use before age 20 and the risk of fibroadenoma [103]. The Epstein-Barr virus might play a causative role in the development of this tumor in immunosuppressed patients [104].…”

Association between HPV, CMV, EBV and HS Viruses and Breast Cancer in Saudi Arabia

“…Breast cancer has epidemiological resemblances to young-adult Hodgkin lymphoma [93][94][95], though indication for breast cancer involves timing of initial EBV infection rather than viral oncogenesis [93]. EBV was found in benign breast tumors in immunosuppressed patients [96], and in vitro, breast epithelial cells were infected by direct contact with EBV-bearing lymphoblastoid cell lines [97]. Moreover, the identification of EBV genes or gene products within breast tumors' tissues represents strong evidence for an EBV-breast cancer association [98].…”