Validation of Six Genetic Determinants of Susceptibility to Estrogen-Induced Mammary Cancer in the Rat and Assessment of Their Relevance to Breast Cancer Risk in Humans

Colletti, John A.; Leland-Wavrin, Kristin M.; Kurz, Scott G.; Hickman, Maureen Peters; Seiler, Nicole L.; Samanas, Nyssa Becker; Eckert, Quincy A.; Dennison, Kirsten L.; Ding, Ling; Schaffer, Beverly S.; Shull, James D.

doi:10.1534/g3.114.011163

Cited by 15 publications

(18 citation statements)

References 49 publications

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“…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

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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.

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Section: Genetic Variants Determining Responses To Estrogenmentioning

confidence: 99%

Genetic variation in sensitivity to estrogens and breast cancer risk

et al. 2018

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“…It is noteworthy that the Ept2 congenic interval on RNO3 extends from D3Mgh21 (48.4 Mb) to D3Rat142 (171.5 Mb) and overlaps almost entirely with Emca5 , a mammary cancer susceptibility QTL that was mapped in an intercross between susceptible ACI and resistant BN rats (Figure 7) (Colletti et al 2014; Kurz et al 2008; Schaffer et al 2006; Strecker et al 2005). Data presented herein as well as data published previously indicate that COP alleles across the Ept2 congenic interval do not impact susceptibility to E2-induced mammary cancer, whereas BN alleles across the Emca5 congenic interval dramatically reduce mammary cancer susceptibility (Colletti et al 2014; Kurz et al 2008). Together, these data suggest that the genetically related ACI and COP rat strains share alleles at Emca5 .…”

Section: Discussionmentioning

confidence: 99%

“…Together, these data suggest that the genetically related ACI and COP rat strains share alleles at Emca5 . The peak LOD region of Emca5 is orthologous to a breast cancer risk locus mapped to human chromosome 20q11 that spans three genes, ASIP , RALY and EIF2S2 (Schaffer et al 2006; Colletti et al 2014; Siddiq, et al 2012). ASIP encodes Agouti Signaling Protein, which regulates skin and hair pigmentation in humans and multiple other mammalian species, including rats (Bonilla, et al 2005; Kanetsky, et al 2002; Suzuki 2013).…”

Section: Discussionmentioning

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: 91%

“…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: 91%

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

Dennison¹,

Samanas²,

Harenda³

et al. 2015

Endocrine-Related Cancer

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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.

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