Expression of the int-1 gene in transgenic mice is associated with mammary gland hyperplasia and adenocarcinomas in male and female mice.

Publisher Summary This chapter reviews the sequence of cellular and other changes during cancer development in selected sites in experimental animals and in humans. It highlights the similarities and differences among the carcinogenic processes and discusses the evident generalities and working hypotheses derived from the analyses. It also discusses some perspective concerning the possible relationship of carcinogenesis to other types of chronic pathological processes such as some forms of adaptation and evolution. Major emphasis is given to three sites—namely, skin, liver, and breast. Several other sites or types of neoplasms are also discussed in the chapter, including urinary bladder, brain, kidney, uterine cervix, and foreign-body sarcoma. It focuses on the development of cancer with chemicals in experimental animals and in humans. To date, the major evidence for a beneficial role for new cell populations occurring during the preneoplastic phase of carcinogenesis concerns the liver. However, it seems appropriate to explore other systems from this point of view. In other organs or tissues, appropriate physiological or environmental factors should be sought as possible influences on early carcinogen-induced new cell populations. These influences might well constitute naturally occurring “promoting” environments in at least some carcinogenic process.

The sequential analysis of cancer development.

It is unequivocal that prolactin is an influential hormone in murine mammary tumorigenesis The Berenblum hypothesis (7), a well-known theoretical model of tumorigenesis that depicts this oncogenic process as a two-step mechanism, ie, initiation and promotion, is a conceptual scheme in which the action of prolactin in mammary tumorigenesis may be understood According to this conceptual model, prolactin would participate in both the initiation and promotion steps of mammary tumorigenesis, In the initiation phase, variations in prolactin secretion appear to influence the metabolism of the mammary epithelium, so that the epithelium would be either more receptive to or refractory to an initiating agent (eg, chemical carcinogen, physical carcinogens, oncogenic viruses, ets) ie, a permissive action In the promotion phase, prolactin may act as either a promoter or an antipromoter of the "transformed" mammary epithelium In promotion, the hormone may either directly or indirectly (via the ovary) stimulate mitotic activity of the "transformed" epithelium In antipromotion the hormone, in the presence of requisite hormones (eg, glucocorticoids), may synergistically induce differentiation (eg, lactation) in the "transformed" epithelium A tumor would result in the former (promotion) but not in the latter (antipromotion) case Whether or not prolactin is significantly influential in human breast tumorigenesis remains to be determined This is an extremely important area of research which is justifiably receiving increased attention For if prolactin can be shown to influence human breast epithelium in a manner similar to its effect on rodent mammary tissue, then prophylactic and/of chemotherapeutic control of human breast tumorigenesis may be feasible by appropriate drug-mediated prolactin suppression

https://cancerres.aacrjournals.org/content/canres/37/4/951.full.pdf

Prolactin and Murine Mammary Tumorigenesis: A Review

Publisher Summary This chapter summarizes briefly the past literature on the studies of spontaneous mouse mammary cancer and discusses in detail the discoveries that have been made only recently. Mammary tumor studies on mice began with the first description of such tumors in a wild mouse in the year 1854. This is an area of tumor biology that was studied first by pathologists, was nurtured by geneticists and endocrinologists, and is only lately being pursued vigorously by investigators from other disciplines such as virology, immunology, biochemistry, molecular biology. Mouse mammary tumors offer many advantages for tumor biological studies. The chapter also talks about mammary tumor virus (MTV), their hormonal influences on mouse mammary neoplasia, and the two categories of inbred strains of mice employed in mammary cancer research—susceptible strains and resistant strains. The mouse mammary tumor system still remains an area of interest to researchers from different disciplines. One of the great advantages of this system remains the amenability of the host animals to laboratory experimentation.

Mammary Neoplasia in Mice

The retroviral capacity for integration into the host genome can give rise to endogenous retroviruses (ERVs): retroviral sequences that are transmitted vertically as part of the host germ line, within which they may continue to replicate and evolve ERVs represent both a unique archive of ancient viral sequence information and a dynamic component of host genomes As such they hold great potential as informative markers for studies of both virus evolution and host genome evolution Numerous novel ERVs have been described in recent years, particularly as genome sequencing projects have advanced This review discusses the evolution of ERV lineages, considering the processes by which ERV distribution and diversity is generated The diversity of ERVs isolated so far is summarised in terms of both their distribution across host taxa, and their relationships to recognised retroviral genera Finally the relevance of ERVs to studies of genome evolution, host disease and viral ecology is considered, and recent findings discussed

The evolution, distribution and diversity of endogenous retroviruses.

Mouse mammary tumor virus-producing cultures of mouse mammary tumor cells synthesize a viral-related polypeptide of molecular weight of 73,000 (gp 73) which is rapidly labeled during a short pulse but disappears during the chase concomitantly with the appearance of label in the virion glycoproteins gp 49 and gp 37.5/33.5. The addition of the protein synthesis-inhibitor cycloheximide to the chase medium has little effect on this conversion. Treatment of the proposed precursor with α-chymotrypsin leads to the formation of a polypeptide of molecular weight 49,000, similar to the major virion glycoprotein. A comparison of tryptic digest maps of the glycoproteins involved supports the hypothesis that both the viral glycoproteins gp 49 and gp 37.5/33.5 are derived from gp 73.

Identification of a precursor protein to the major glycoproteins of mouse mammary tumor virus.

Mammary tumor virus (MTV) replication was confined primarily to cells organized as acini in intact mouse mammary glands. Primary mammary tumors maintained a high degree of acinar organization and cells therein continued to replicate MTV vegetatively. Nonacinar mammary cells, derived by serial transplantation of acinar tumor cells, no longer actively replicated MTV. This suggests that phenotypic differences exist among mammary epithelial cells in their ability to support virus replication, that a fundamental relationship exists between the organization of epithelium for secretion and active virus replication, and that this relationship is not altered as a primary consequence of neoplastic transformation. Mammary epithelial cells from pregnant, non-tumor-bearing, MTV-infected BALB/cfC3H mice or from acinar mammary tumors from a number of mouse strains were grown in primary monolayer cultures. Such cell cultures under the influence of insulin and cortisol exhibited the ability to organize into discrete three-dimensional structures called “domes.” MTV replication in such cultures took place primarily in cells within the organized domes. Cells cultured from nonacinar tumors did not exhibit any propensity to organize into domes, nor did they replicate MTV in primary culture. This suggests that the cell organizational requirement for MTV replication observed in vivo is conserved in primary culture. Dome formation is not an effect of virus replication, as cells from uninfected BALB/c animals organized into domes in culture without concomitant MTV replication. Growth-regulating signals, exerted between contiguous cells in cultures of non-MTV-infected mammary epithelium, were not modified by the occurrence of active virus replication nor as a direct consequence of neoplastic transformation. Cells derived from nontumor BALB/cfC3H glands and from spontaneous tumors exhibited cell growth kinetics, saturation densities, and deoxyribonucleic acid synthesis kinetics nearly identical to those of noninfected normal mammary epithelium in primary culture. Cell to cell growth regulatory signals were modified in cultures of nonalveolar tumor cells wherein evidence of overgrowth is documented.

Relationship between organization of mammary tumors and the ability of tumor cells to replicate mammary tumor virus and to recognize growth-inhibitory contact signals in vitro.

Mouse mammary tumor virus polypeptides were detected in the cytoplasm of mouse mammary tumor cell cultures using immunological precipitation techniques. The anti-mouse mammary tumor virus serum precipitated the major virion glycoproteins gp49 and gp37.5/33.5 and a viral-related nonvirion glycoprotein of 76,000 daltons. Subcellular fractionation studies revelaed that the cell-associated virion glycoproteins were present in the membrane fraction. Pulsechase experiments indicated that a viral-related nonvirion glycoprotein of 76,000 daltons may be a precursor to one or more of the virion glycoproteins.

S. Nandi

Papers

Mammary Neoplasia in Mice

Identification of a precursor protein to the major glycoproteins of mouse mammary tumor virus.

Relationship between organization of mammary tumors and the ability of tumor cells to replicate mammary tumor virus and to recognize growth-inhibitory contact signals in vitro.

Intracellular synthesis of mouse mammary tumor virus polypeptides: indication of a precursor glycoprotein.

Identification ofaPrecursor Protein totheMajorGlycoproteins ofMouseMammaryTumorVirus