Mapping of Three Genetic Determinants of Susceptibility to Estrogen-Induced Mammary Cancer within the <i>Emca8</i> Locus on Rat Chromosome 5

Schaffer, Beverly S.; Leland-Wavrin, Kristin M.; Kurz, Scott G.; Colletti, John A.; Seiler, Nicole L.; Warren, Christopher L.; Shull, James D.

doi:10.1158/1940-6207.capr-12-0346-t

Cited by 17 publications

(23 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The existence of each of these mammary tumor QTL has been confirmed through generation and characterization of congenic rat strains. The QTL exhibit orthology to a region of the human genome that has been linked to breast cancer risk and/or mammographic breast density in genome wide association studies, strongly suggesting these genetically defined rat models are relevant to understanding the genetic bases of breast cancer susceptibility in humans (Colletti et al 2014; Schaffer et al 2013). …”

Section: Genetic Variants Determining Responses To Estrogenmentioning

confidence: 99%

Genetic variation in sensitivity to estrogens and breast cancer risk

et al. 2018

Self Cite

View full text Add to dashboard Cite

Breast cancer risk is intimately intertwined with exposure to estrogens. While more than 160 breast cancer risk loci have been identified in humans, genetic interactions with estrogen exposure remain to be established. Strains of rodents exhibit striking differences in their responses to endogenous ovarian estrogens (primarily 17β-estradiol). Similar genetic variation has been observed for synthetic estrogen agonists (ethinyl estradiol) and environmental chemicals that mimic the actions of estrogens (xenoestrogens). This review of literature highlights the extent of variation in responses to estrogens among strains of rodents and compiles the genetic loci underlying pathogenic effects of excessive estrogen signaling. Genetic linkage studies have identified a total of the 35 quantitative trait loci (QTL) affecting responses to 17β-estradiol or diethylstilbestrol in 5 different tissues. However, the QTL appear to act in a tissue-specific manner with 9 QTL affecting the incidence or latency of mammary tumors induced by 17β-estradiol or diethylstilbestrol. Mammary gland development during puberty is also exquisitely sensitive to the actions of endogenous estrogens. Analysis of mammary ductal growth and branching in 43 strains of inbred mice identified 20 QTL. Regions in the human genome orthologous to the mammary development QTL harbor loci associated with breast cancer risk or mammographic density. The data demonstrate extensive genetic variation in regulation of estrogen signaling in rodent mammary tissues that alters susceptibility to tumors. Genetic variants in these pathways may identify a subset of women who are especially sensitive to either endogenous estrogens or environmental xenoestrogens and render them at increased risk of breast cancer.

show abstract

Section: Genetic Variants Determining Responses To Estrogenmentioning

confidence: 99%

Genetic variation in sensitivity to estrogens and breast cancer risk

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…All rats were housed under controlled temperature, humidity, and 12-hr light/12-hr dark conditions in facilities that were accredited by the American Association for Accreditation of Laboratory Animal Care and operated in accordance with The Guide for the Care and Use of Laboratory Animals . All procedures related to the care, propagation, genotyping, treatment with E2, evaluation for presence of mammary cancer and assessment of pituitary hyperplasia/adenoma have been described (Gould et al 2004; Harvell et al 2000; Schaffer et al 2006; Schaffer et al 2013; Shull et al 2001; Shull et al 1997; Spady et al 1998). The number of grossly discernible tumors, i.e., approximately 1 mm in diameter, was quantified at necropsy.…”

Section: Methodsmentioning

confidence: 99%

“…Multiple quantitative trait loci (QTLs), designated Emca1 ( E strogen-induced m ammary ca ncer ) through Emca9 , that harbor genetic determinants of susceptibility to E2-induced mammary cancer have been mapped in intercrosses between susceptible ACI rats and resistant COP or BN rats (Gould, et al 2004; Schaffer, et al 2006; Shull 2007). The existence of these Emca loci has been confirmed by generation and characterization of congenic rat strains that harbor alleles from the resistant COP or BN strain on the genetic background of the susceptible ACI strain (Colletti, et al 2014; Schaffer, et al 2013). Moreover, each of the Emca loci is orthologous to genetic determinants of breast cancer risk mapped in genome wide association studies (Colletti et al 2014; Schaffer et al 2013).…”

Section: Introductionmentioning

confidence: 92%

“…The existence of these Emca loci has been confirmed by generation and characterization of congenic rat strains that harbor alleles from the resistant COP or BN strain on the genetic background of the susceptible ACI strain (Colletti, et al 2014; Schaffer, et al 2013). Moreover, each of the Emca loci is orthologous to genetic determinants of breast cancer risk mapped in genome wide association studies (Colletti et al 2014; Schaffer et al 2013). These data strongly suggest that these rat models of E2-induced mammary cancer share multiple genetic determinants of breast cancer risk with humans.…”

Section: Introductionmentioning

confidence: 92%

See 1 more Smart Citation

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

Dennison¹,

Samanas²,

Harenda³

et al. 2015

Endocrine-Related Cancer

View full text Add to dashboard Cite

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.

show abstract

“…Silastic™ tubing implants containing the synthetic estrogen DES were prepared as described previously and were surgically inserted into 9-week-old male rats (Gould et al 2006; Kurz et al 2008; Shull et al 2007; Spady et al 1999c; Strecker et al 2005). Female rats were similarly treated using Silastic™ implants containing 17β-estradiol (E2) (Shull et al 1997; Gould et al 2004; Schaffer et al 2006; Schaffer et al 2013). The control animals received empty implants.…”

Section: Methodsmentioning

confidence: 99%

Ept7 influences estrogen action in the pituitary gland and body weight of rats

et al. 2014

Self Cite

View full text Add to dashboard Cite

Estrogens control many aspects of pituitary gland biology, including regulation of lactotroph homeostasis and synthesis and secretion of prolactin. In rat models, these actions are strain specific and heritable, and multiple quantitative trait loci (QTL) have been mapped that impact the responsiveness of the lactotroph to estrogens. One such QTL, Ept7, was mapped to RNO7 in female progeny generated in an intercross between BN rats, in which the lactotroph population is insensitive to estrogens, and ACI rats, which develop lactotroph hyperplasia/adenoma and associated hyperprolactinemia in response to estrogen treatment. The primary objective of this study was to confirm the existence of Ept7 and to quantify the impact of this QTL on responsiveness of the pituitary gland of female and male rats to 17β-estradiol (E2) and diethylstilbestrol (DES), respectively. Secondary objectives were to determine if Ept7 influences the responsiveness of the male reproductive tract to DES and to identify other discernible phenotypes influenced by Ept7. To achieve these objectives, a congenic rat strain that harbors BN alleles across the Ept7 interval on the genetic background of the ACI strain was generated and characterized to define the effect of administered estrogens on the anterior pituitary gland and male reproductive tissues. Data presented herein indicate Ept7 exerts a marked effect on development of lactotroph hyperplasia in response to estrogen treatment, but does not affect atrophy of the male reproductive tissues in response to hormone treatment. Ept7 was also observed to exert gender specific effects on body weight in young adult rats.

show abstract

Mapping of Three Genetic Determinants of Susceptibility to Estrogen-Induced Mammary Cancer within the Emca8 Locus on Rat Chromosome 5

Cited by 17 publications

References 73 publications

Genetic variation in sensitivity to estrogens and breast cancer risk

Genetic variation in sensitivity to estrogens and breast cancer risk

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

Ept7 influences estrogen action in the pituitary gland and body weight of rats

Contact Info

Product

Resources

About