Development and characterization of a novel rat model of estrogen-induced mammary cancer

Abstract

The ACI rat model of 17β-estradiol (E2)-induced mammary cancer is highly relevant for use in establishing the endocrine, genetic and environmental bases of breast cancer etiology and identifying novel agents and strategies for preventing breast cancer. E2 treatment rapidly induces mammary cancer in female ACI rats and simultaneously induces pituitary lactotroph hyperplasia and adenoma. The pituitary tumors can result in undesired morbidity which compromises long term studies focused on mammary cancer etiology and prevention. We have defined the genetic bases of susceptibility to E2-induced mammary cancers and pituitary tumors and have utilized the knowledge gained in these studies to develop a novel inbred rat strain, designated ACWi, that retains the high degree of susceptibility to E2-induced mammary cancer exhibited by ACI rats but lacks the treatment related morbidity associated with pituitary lactotroph hyperplasia/adenoma. When treated with E2, female ACWi rats developed palpable mammary cancer at a median latency of 116 days, an incidence of 100% by 161 days and exhibited an average of 15.6 mammary tumors per rat following 196 days of treatment. These parameters did not differ from that observed for contemporaneously treated ACI rats. None of the E2 treated ACWi rats were euthanized prior to the intended experimental end point due to any treatment related morbidity other than mammary cancer burden, whereas 20% of contemporaneously treated ACI rats exhibited treatment related morbidity that necessitated premature euthanasia. The ACWi rat strain is well suited for use by those in the research community focusing on breast cancer etiology and prevention.

Genetic variation in sensitivity to estrogens and breast cancer risk

“…Each of the QTL mapped in these studies of estrogen action on the pituitary lactotroph resides in a distinct region of the rat genome, although the mapping resolution for Edpm3 and Ept2 , both of which reside on rat chromosome 3, is insufficient to demonstrate conclusively that these two QTL are distinct entities. Several of these QTL that harbor genetic determinants of responsiveness of the rat pituitary gland to estrogens have been isolated as congenic rat strains, which will allow the genetic variants that impact responsiveness to estrogens to be mapped to higher resolution and their molecular actions to be further elucidated (Dennison et al 2015; Kurz et al 2014; Kurz et al 2008; Pandey et al 2004; Wendell et al 2002). The presence of multiple loci regulating responses to estrogens and that these are distinct for mammary gland and uterus highlights the tissue-specific nature of estrogen signaling and its complexity.…”

“…For example, the QTL that influence development of pituitary lactotroph hyperplasia/adenoma are physically distinct from those that influence susceptibility to mammary cancer; the only exception being Ept7 and Emca4 , which both map to the same region of rat chromosome 7 (Kurz et al 2014; Schaffer et al 2006; Shull et al 2007). The tissue-specific actions of these loci allowed development of a novel rat model of 17β-estradiol-induced mammary tumors that lacks the deleterious morbidities associated with pituitary lactotroph hyperplasia/adenoma (Dennison et al 2015). As a result, studies of regulation of estrogen signaling must be studied in the appropriate tissue.…”

Ept7, a quantitative trait locus that controls estrogen-induced pituitary lactotroph hyperplasia in rat, is orthologous to a locus in humans that has been associated with numerous cancer types and common diseases

“…Pituitary weight, a surrogate indicator of absolute lactotroph number, was measured as the primary phenotypic indicator of lactotroph responsiveness to E2 [ 20 , 29 , 35 , 36 , 38 ]. Pituitary weight for sham treated control rats across all 21 rat strains examined in this study averaged 9.8 mg (standard error of the mean = 0.2; n = 105).…”

“…Female rats from each rat strain were treated with 17β-estradiol (E2) beginning at 9 weeks of age as described previously [ 38 – 42 ]. Control rats from each strain received empty implants.…”

“…The pituitary gland was collected at necropsy, weighed, and photographed. Pituitary weight has been shown to correlate with pituitary DNA content and the level of circulating prolactin, and thereby serves as a surrogate indicator of absolute lactotroph number [ 20 , 29 , 35 , 36 , 38 ].…”