Is mouse mammary tumor virus an etiologic agent of human breast cancer and lymphoma?

In this issue of the Journal, Quilon et al present a patient with synchronous invasive breast cancer and low-grade lymphoma. There was no evidence of lymphoma outside the breast, and the two neoplasms demonstrated collision histology. The question is whether their case simply represents a chance unusual occurrence, whether the two tumors may have a common etiology, or whether one neoplasm gave rise to the other in some unknown fashion. One possibility is that the lymphoma began as an immunologic reaction to the breast cancer. It is well known that many neoplasms have a better prognosis when accompanied by a non-neoplastic lymphoid infiltration. On the other hand, there is precedent for adenocarcinoma and low-grade lymphoma in the same organ (stomach) being caused by the same infectious organism (Helicobacter pylori).

We reported that lymphoma occurred in women with breast cancer more frequently than previously appreciated, and that when both diseases afflicted the same woman, the lymphoma almost always was diagnosed simultaneously with or after the breast cancer. (1) That report was based on 87 patients with both diseases. To date, we have identified 130 patients with both neoplasms, and all conclusions reported in our initial publication are validated by analyzing the larger group of patients now available. The question of course is, what does the development of two completely different malignancies in the same patient mean?

In the same year, we published a study in which we demonstrated that approximately one-third of women with breast cancer have mouse mammary tumor virus (MMTV)-like envelope (ENV) gene sequences in the DNA of their breast cancer, but not in nonmalignant tissues. (2) We included in that paper data on one patient with breast cancer and non-Hodgkin lymphoma that had the MMTV-like ENV sequences in the DNA of both tumors. This finding was extremely interesting to us since in addition to being the etiologic agent of breast cancer in inbred mice, (3) MMTV, a beta retrovirus, is also a cause of lymphoma in mice. (4) Subsequently, we collected paraffin blocks from other patients with both tumors and found MMTV-like ENV sequences in the breast cancer and lymphoma tissue of 6 of 12 patients studied. (5) In addition, we have found MMTV-like ENV gene sequences in non-Hodgkin lymphomas (NHL) of 3 of 19 patients diagnosed with only lymphoma. (2)

Subsequent to our earlier reports, an increasing number of case reports of patients with breast cancer and NHL have appeared, and all are simultaneous presentations of both diseases. (6-12) In addition, Tanaka et al reported that Japanese women with breast cancer had a 3.5-fold increased risk of developing non-Hodgkin lymphoma. (13) However, unlike our patients who had only rarely received chemotherapy for breast cancer, (1) the increased incidence of NHL in patients studied by Tanaka et al, appeared to apply primarily to patients who received breast cancer chemotherapy.

Although still controversial, (14,15) there is an increasing body of laboratory (16,17,18) and epidemiologic (19,20) evidence that supports the hypothesis that MMTV may be important in the development of some human breast cancers and other diseases. In addition, in the mouse system there is a very close association of MMTV and lymphoid cells. The primary targets for exogenous MMTV infection in the mouse are the T and B cells located in the Peyer patches of the gastrointestinal tracts of neonatally infected pups. (21) A recent Russian paper reports on the detection of MMTV-like ENV gene sequences in a human mammary carcinoma patient's intestinal lymphoid tissue. (22) Two of our breast cancer and lymphoma patients had small bowel lymphomas. The MMTV-like retroviral sequences that have been reported in primary biliary cirrhosis patients appear to be preferentially located in lymphoid tissues with a limited viral abundance in liver where end organ damage occurs in this disease. (23) Similarly, human breast tumors appear to have a limited abundance of MMTV-like sequences, whereas the presence of MMTV-like sequences has been reported in human lymphocytes of breast cancer patients. (24,25) These results argue for the ability of MMTV to infect human lymphoid tissue. If indeed such infection of human B and T-cells can occur, this may allow not only for passage of MMTV to the breast, but also for MMTV to function as an etiologic agent of neoplastic transformation of lymphoid tissue itself.

Similar to the membrane proteins of bovine leukemia virus gp30, (26) Epstein-Barr virus LMP2A, (27) and Kaposi sarcoma virus K1, (28) MMTV's ENV gene is a membrane protein that contains immunoreceptor tyrosine-based activation motifs (ITAM) domains. (29) Normally ITAM domains function in hemopoietic cells as immunoreceptor tyrosine-based activation motifs that are signaling motifs associated with activation, survival, and differentiation. (30) The ITAM containing motifs of gp30, LMP2A, and K1 have been shown to be capable of cell transformation. (31,32) Recently published data have shown that the ITAM-containing MMTV ENV protein of mice can transform in vitro both mouse and human breast tissue. (29) These studies implicate ITAM-containing proteins as oncoproteins. The MMTV ENV sequences that we have detected in both human breast tumors and non-Hodgkin lymphomas all contain this ITAM domain and should theoretically also be capable of transformation. (5) A very curious additional finding is that all the MMTV ENV sequences that have been isolated from the human non-Hodgkin lymphomas so far studied contain an identical one nucleotide change at the same location with the ITAM domain. Our current goal is to determine if MMTV ITAM-containing ENV gene sequences isolated from our breast cancer and non-Hodgkin lymphoma patients are capable of cell transformation. If such sequences are found to be involved in transformation through signaling motifs, then perhaps such a molecular mechanism could be interrupted and result in successful treatment of these malignancies.

The plot thickens. Holland et al reported at the recent national meeting of the American Society of Clinical Oncology that human breast cancer cells containing MMTV-like sequences can infect normal human breast cancer cells (free of virus) and normal human mononuclear blood cells in vitro. (33) These results strongly suggest that MMTV is an infectious agent of human tissues.

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33. Holland JF, Wang Y, Mellana S, et al. Identification of a retrovirus in human breast cancer [abstract]. Proc Am Soc Clin Oncol 2005;23:15s.</p> <pre> To live a creative life, we must lose our fear of being wrong. --Joseph Chilton Pearce </pre> <p>Peter H. Wiernik, MD, and Polly R. Etkind, PHD

From the OLM Comprehensive Cancer Center, New York Medical College, Bronx, NY.

Reprint requests to Peter Wiernik, MD, OLM Comprehensive Cancer Center New York Medical College, Bronx, NY 10466. Email: [e-mail]

Accepted August 22, 2005.