Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2001-12-19
2003-12-30
Stucker, Jeffrey (Department: 1648)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C435S005000, C435S006120, C435S007920, C435S320100, C435S455000, C435S330000, C435S331000, C435S332000, C435S339100, C435S975000, C436S516000, C424S187100, C424S207100, C530S350000, C530S388350, C530S387900, C530S388800, C530S389400, C530S389700, C530S826000
Reexamination Certificate
active
06670466
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to compositions and methods for the detection, prognostic evaluation, and treatment of oncogenic disorders, particularly breast cancer.
Specifically, the instant invention provides for compositions, useful for identifying and treating disorders related to newly identified endogenous retroviruses which are present in a subset of humans, cats, and nonhuman primates.
2. Technical Problem Addressed by the Invention
Mutations in Known Susceptibility Genes do not Account for all Breast Cancer
Breast cancer (BC) is one of the leading causes of cancer death among women. The as induction of BC is thought to involve the interplay of several factors, including the genetic, hormonal, immunological and physiological status of the host, as well as dietary habits and exposures to chemicals, radiation or infectious agents. It is now clear that variations of several genes, including BRCA-1 and BRCA-2, can result in greatly increased risks for development of BC. However, defects in known BC susceptibility genes account for only about 5% of BC, the so-called familial cases (Armstrong et al., 2000; Gayther et al., 1998).
As with other types of cancer, the possibility that a virus is etiologically involved in sporadically occurring BC has not been eliminated. Consequently, there has long been a need to determine which, if any viruses are causally linked to the development of BC. The identification of such a virus would likely provide invaluable aid in the following areas BC medicine: prevention, diagnosis, determination of prognosis, and treatment.
3. Description of Related Art
Retrovirus Induction of Breast Cancer in Mice
Mouse mammary tumor virus (MMTV), a B-type retrovirus, was discovered during studies of hereditary cancer in mice at the Jackson Laboratories in the 1930's (Bittner, 1936). As the prototype of slow-transforming retroviruses, MMTV has been definitively shown to cause BC in mice. Prior studies established that MMTV is transmitted both in the gerinline as endogenous proviruses and exogenously via milk. As endogenous elements MMTV proviruses follow patterns of Mendelian inheritance, as other sequences in the genome (Cohen et al., Cell,1979; Cohen and Varmus, 1979, 1980; Traina et al., 1981; Traina-Dorge and Cohen, 1983; Traina-Dorge el al., 1985; Varmus et al., 1978). Horizontal transmission of MMTV typically occurs by infection of mouse pups by MMTV virions present in the milk of infected dams. Thus, it is possible to transmit MMTV to mice by foster feeding. 30 or more unique proviral integration sites for endogenous MMTV have been identified. However, some wild mice do not carry any endogenous MMTV proviruses (Cohen and Varmus, 1979; Cohen et al, 1982). This result suggests that the many endogenous MMTV proviruses are relatively recent additions to the mouse genome. The most likely explanation is that MMTV entered the germline of certain mice (but not others) on multiple occasions after the evolutionary splits among the various species and subspecies of the genus Mus. Certain endogenous MMTV can be activated by hormones to form infectious virions capable of inducing mammary carcinomas after long latency periods. Most endogenous MMTV proviruses are defective and do not encode for infectious virions.
Roles of MMTV Genes and Cellular Genes in Oncogenesis
The MMTV Orf protein can function as a superantigen (SA). When expressed in the thymus during fetal/early development it can mediate complete or incomplete deletion of SA-reactive T-cells. SA expression is required to activate B-cells targets of MMTV in the gut-associated lymphoid tissue of nursing pups. Complete deletion of the SA responsive clones thus renders the mice resistant to MMTV infection in the gut and thereby leads to a low incidence of MMTV-induced tumors. On the other hand, in mice with only partially deleted responsive clones of lymphoid cells the SA activation stimulates expansion of the targets and spread of MMTV. As female infected animals reach puberty, estrogenic hormones drive expression of the MMTV long terminal repeat (LTR) through its hormone response element (HRE). This permits production and assembly of MMTV and spread of the virus to other hormonally-sensitive tissues, including the breast and ovaries. Integration of MMTV LTRs adjacent to certain cellular genes, such as the proto-oncogenes Int, Wnt and Fgf, can increase expression of these genes resulting in BC and other cancers.
The molecular genetic interactions between MMTV, the immune system of its murine host, and the breast and other hormonally-sensitive cells malignantly transformed by this retrovirus have been extensively studied. MMTV promotes mammary gland cancer in mice by insertional mutagenesis (Varmus et al., 1978; Varmus, 1985). MMTV proviral LTR elements direct steroid hormone-dependent transactivation of various cellular oncogenes including Wnt, Fgf and Int thereby promoting clonal expansion of tumor cells (Shackleford and Varmus, 1987, Shackleford et al, 1993; Jakobovits et al., 1986; Nusse, 1991; Nusse et al.,1985). For productive, persistent infection and completion of its replication cycle, MMTV must contain a superantigen and interact with a functional host immune system (Golovkina et al., 1995; Luther and Acha-Orbea, 1996; Coffin, 1992).
The Search for a Human Breast Cancer Virus
The discovery of the oncogenic MMTV has prompted many investigators to explore a retroviral etiology for BC in humans (Sarkar, 1980). Data collected over the past five decades has suggested the existence of a human homologue of MMTV. In 1971, Moore and associates reported that 60% of human milk samples from BC patients contain B-type particles indistinguishable from MMTV by electron microscopy, compared to 5% of the general population (Moore et al., 1971). These investigators also reported that 39% of Parsi women of India, an inbred population with a two-fold increased incidence of BC, had B-type particles in their milk (Das et al., 1972; Moore, 1971). Several studies have demonstrated that BC cells, but not cells from normal tissues, also contain reverse transcriptase (RT), an enzyme associated with all retroviruses. Numerous investigators have examined serum and breast milk for the presence of antibodies reactive with MMTV. Most of these studies were performed in the pre-AIDS era, prior to the advent of highly sensitive and specific techniques for detecting anti-retroviral antibodies made necessary for detection of HIV antibodies in donated blood.
Despite the numerous electron microscopic, biochemical and immunological studies on human breast carcinoma tissue, milk, patients' sera, and breast carcinoma cell lines suggesting the existence of a human homologue of MMTV, proof that such an agent exists has remained elusive (Andersson et al., 1996; Ziegler, 1997). Most authors have dismissed the importance of prior studies purporting to show evidence of a human homologue of MMTV because of the presence of numerous human endogenous retroviruses (HERVs) (Larsson et al, 1994; Li et al., 1996; Lower et al., 1996; Meese et al., 1996; Ono, 1986; Patience et al., 1996; Faff et al., 1992). There are about 50,000 HERVs or HERV-related sequences in the human genome, some of which have been shown to have up to 60% homology to MMTV. In this regard, it is important to note that seroreactivity to HERV-K10, to this point the HERV considered to be most closely related to MMTV, cannot account for MMTV-reactive antibodies present in the sera of breast cancer patients and the smaller number of healthy individuals (Vogetseder et al., 1995). Furthermore, we believe that the presence of these MMTV-related sequences is precisely the reason that human homologues of MMTV have not previously been demonstrated conclusively by molecular techniques. The presence of these related, but distinct, sequences could have obscured the detection of more closely related sequences by prior investigators who used less sensitive techniques, such as Southern blotting.
Only recently have sequences with relativel
Howrey Simon Arnold & White , LLP
Stucker Jeffrey
The Administrators of the Tulane Educational Fund
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