ROLE OF MMTV INTEGRATION LOCUS CELLULAR GENES IN BREAST CANCER

Rajeshwar Rao Tekmal, and Nagalakshmi Keshava

Department of Gynecology and Obstetrics and Winship Cancer Center, Emory University School of Medicine, Atlanta, GA 30322-4710, USA

Received 10/14/97 Accepted 10/17/97

2. INTRODUCTION

Breast cancer is one of the most common malignancy in women with the incidence rate as high as one in every eight women (1). Several factors are associated with this disease such as genetics, life style, menstrual and reproductive history, long term treatment with estrogens. Genetic abnormalities include germline mutations, gene amplifications, rearrangements, overexpression, deletions or point mutations. The genes thought to be involved in human breast cancer encode growth factors, receptors, nuclear transcription factors, cell cycle regulatory proteins, tumor suppressor proteins and others. It is possible that these factors alone or in combination could provide a selective environment for the clonal outgrowth of mammary epithelial cells containing mutations.

Unlike retroviruses that carry a transduced oncogene (v-myc, v-erb, v-Ha-ras etc.), other retroviruses including avian leukosis virus (ALV), murine leukemia virus (MLV) and mouse mammary tumor virus (MMTV) does not carry a transduced oncogene and tumorigenesis is due to insertional mutagenesis. Tumorigenesis by these viruses mainly depends on the host cellular oncogenes, transcriptionally activated or otherwise mutated as a consequence of proviral integration. MMTV is considered as a biological carcinogen that induces tumor development as a consequence of insertional mutagenesis (2, see latest review for more information). MMTV is of special interest in studying the mechanism of mammary tumorigenesis. MMTV-infected mice develop initially preneoplastic hyperplastic alveolar nodules (HAN). These nodules, and also the primary tumor that develop within these hyperplasias, are hormone-dependent and are evoked by pregnancy and regress after parturition. After several cycles of pregnancy, tumors arise that eventually become hormone independent (3). MMTV induces mammary tumors by acting as an insertional mutagen, and activating transcription of the nearby genes. MMTV acts as a insertional mutagen that causes the deregulation of expression of adjacent cellular genes (named as int genes) in mammary tumors. Molecular analysis of proviral integration site in tumors has led to the discovery of a number of cellular proto-oncogenes such as several members of the fibroblast growth factor (FGF) family, wnt genes and others like NOTCH gene. Tumorigenesis by exogenous MMTV is accompanied by insertion of the proviral MMTV into the host genome. Several animal models have been used to study this mechanism. Inbred strains with high incidence of mammary tumors such as C3H, GR, BR6 and RIII mouse strains are intentionally used (4,5). MMTV in these mice is transmitted in two ways: In the GR mouse strain, the virus is transmitted endogenously via the germ line since these mice contain an endogenous MMTV locus on chromosome 18, Mtv-2, which expresses the MMTV provirus at high levels. In most other susceptible mouse strains, like C3H and BR6, MMTV expression in the mammary gland of an infected female is markedly increased during lactation under the influence of steroid hormones. As a result, MMTV is secreted in the mother's milk and transmitted exogenously to the offspring, probably through the gut epithelium (3). Parous C3H females develop pregnancy-independent mammary tumors. In addition, MMTV (C3H)-infected females frequently develop mammary preneoplastic HANs, whereas uninfected females infrequently developed HANs (6-8). The GR, BR and RIII females have a high incidence of pregnancy-dependent mammary tumors, or plaques, which after one or more parities develop pregnancy-independent mammary tumors (2). In addition, metastatic lesions in the lungs of MMTV-infected mammary tumor bearing mice have been detected.