Mammary Neoplasia
There is great variation in the incidence of mammary tumors among different strains of mice. For example, the incidence of mammary tumors in the BALB/c strain is low, whereas up to 100% of C3H females develop mammary tumors by the time they reach 9 months of age (Fig.
1.46). Endogenous (as well as exogenous) mammary tumor viruses (MMTVs) play an important role in mouse mammary neoplasia. Chemical carcinogens and hormones also influence the incidence of mammary tumors in laboratory mice. Prolactin, progesterone, and estrogens may all play a role in the development of hormone-responsive mammary tumors. Multiparous FVB mice are prone to development of mammary tumors, which may be related to their pituitary prolactin secretion dynamics. Stress due to conditions such as intensive breeding or overcrowding has been found to have a significant influence on the incidence of mammary neoplasia in C3H/He mice.Spontaneous mouse mammary tumors were originally classified under a scheme developed by Thelma Dunn, using letter designations (A, B, C, AB, L, P, Y, etc.). Subsequently, a tissue-based system (alveolar, ductal, myoepithelial) was used, but both of these schemes were not effective at defining the new types of tumors that are arising in GEMs and relate poorly to human disease. The MMHCC consensus classification uses glandular, acinar, cribriform, papillary, solid, squamous, fibroadenoma, adenomyoepithelioma, adenosquamous, and NOS.
Mammary neoplasia in the mouse is related to inser- tional mutagenesis by MMTVs. MMTVs are either exogenous or endogenous (see "Retroelements and Retrovirus Infections”) but induce similar lesions, although endogenous viruses tend to induce low-grade lesions that arise later in life. Unless purposely introduced and maintained in mouse populations, exogenous MMTVs are not encountered in laboratory mice.
Thus, the viruses of significance for induction of spontaneous mammary neoplasia are the endogenous replication-competent MMTVs that are present in a relatively few strains of mice, including C3H, BALB/c, and GR, among others. Other strains of mice that do not harbor replication-competent MMTV may be susceptible to experimental infection with MMTV, but B6 mice are remarkably resistant. The earliest discernable microscopic lesions are focal and multifocal hyperplasias within the terminal ductule or alveolar buds. Two types of lesions arise in MMTV-infected mice. Hyperplastic alveolar nodules (HANs) resemble prelactating mammary gland but stand out from the background of the nonlactating gland as nodules. Plaques are circumscribed ductal proliferations that appear during pregnancy and regress on parturition. As either of these lesions evolve and become autonomous of hormonal influences, some progress into mammary intraepithelial neoplasias (MINs) (high- or low-grade), adenomas, or carcinomas.Mammary tumors are often multicentric and multinodular in character, well circumscribed, and easily separated from surrounding tissue. The tissue is usually grayish white and soft but may contain blood-filled cysts and areas of necrosis. Tumors with squamous features may contain flaky white material, and others may contain milky secretory product. Despite their circumscribed noninvasive nature, pulmonary metastases are common. There are a variety of patterns seen histologically, which may vary with the strain background of the mouse and the MMTV strain. However, multiple patterns of tumor may arise in a single strain of mouse.
Mammary tumors that are induced in GEMs with onco-transgenes under control of mammary gland promoters, such as MMTV-LTR or whey acidic protein (WAP), follow predictable behaviors (signature pathology). Most notably, those that are induced by Wnt-1 resemble naturally occurring, MMTV-induced tumors. Spontaneous mammary tumors arise from activation of either Wnt-1, Notch4, or Fgf3 proto-oncogenes (which are all members of the Wnt-1 signal transduction pathway) through integration of the MMTV provirus. Wnt-1 or Fgf transgenic mice will develop the full range of tumors that arise spontaneously and often in the same mouse. Other GEMs have tumors of unique phenotype, but they, too, fall within discernable phenotypic (signature) categories that do not resemble MMTV- induced tumors.