An association between a common variant (G972R) in the IRS-1 gene and sex hormone levels in post-menopausal breast cancer survivors

Fan, Jing; McKean‐Cowdin, Roberta; Bernstein, Leslie; Stanczyk, Frank Z.; Li, Arthur Xuejun; Ballard‐Barbash, Rachel; McTiernan, Anne; Baumgartner, Richard N.; Gilliland, Frank D.

doi:10.1007/s10549-006-9211-2

Cited by 4 publications

(3 citation statements)

References 67 publications

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“…In a study on the association between breast density and genetic variations in IGF signaling system, the rare AA genotype was found not to associate with breast density (81). Given that the significance of the crosstalk between the IGF and ER signaling in breast cancer, the association between the genetic variations in IRS-1 and sex hormone levels in post-menopausal breast cancer survivors was studied (82). The GA genotype was only found in African-American patients and positively correlated with estrone, testosterone and free testosterone and negatively correlated with serum hormone binding globulin.…”

Section: ) Irss In Human Breast Cancermentioning

confidence: 99%

Insulin Receptor Substrates (IRSs) and Breast Tumorigenesis

Chan

Lee

2008

J Mammary Gland Biol Neoplasia

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Insulin receptor substrate (IRS)-1 and IRS-2 are adaptor proteins in the insulin-like growth factor I (IGF-I)/IGF-I receptor (IGF-IR) pathway that mediate cell proliferation, migration, and survival. In addition to their role as scaffolding proteins in the cytoplasm, they are able to translocate into the nucleus and regulate gene transcription. IRS levels are developmentally and hormonally regulated in the normal mammary gland and both are essential for normal mammary gland bud formation and lactation. Both IRS-1 and IRS-2 are transforming oncogenes, and induce transformation and metastasis in vitro and in vivo. In breast cancer IRSs have unique functions, with IRS-1 being mainly involved in cell proliferation and survival, whereas IRS-2 has clear roles in cell migration and metastasis. In this review we will discuss the roles of IRSs in mammary gland development and breast cancer. KeywordsInsulin receptor substrate; IRS-1; IRS-2; IRS1; IRS2; mammary gland; tumorigenesis; breast cancer; transformation; transgenic mice 1) The IRS family of proteinsThere are six members of the IRS family of signaling adaptor proteins (IRS-1-6) (1-6). IRS-1 and IRS-2 are widely expressed in tissues, including brain, muscle, heart, adipocyte, kidney, ovary and mammary gland (7-10), whereas IRS 4 is limited to the brain and thymus (5). While IRS-3 is expressed in rodents, a paralog has not been identified in humans (4). IRS-5 and IRS-6 are considered 'distant relatives' from the rest of the family and are more similar to each other than to the other IRS proteins (6).Owing to their wide tissue expression in rodents and humans, IRS-1 and IRS-2 are the most well-studied. IRS-1 and IRS-2 are highly similar to each other in protein structure (2,3,11). Both contain a highly conserved N-terminus, with a plextrin homology (PH) and phosphotyrosine binding (PTB) domains which mediates the binding to insulin receptor (IR) and insulin-like growth factor receptor (IGF-IR) (11)(12)(13)(14)(15). In their C-termini, IRSs contain numerous tyrosine and serine residues that serve as docking sites for Src-homology 2 (SH2) containing proteins (11,(16)(17)(18). Upon phosphorylation of the tyrosine and serine residues, downstream adaptor proteins are recruited and activated (11,19). The best characterized downstream effectors are PI3K and ERK1/2 (20-24). Ligand-activated IGF-IR and IR signaling pathways that involve direct IRS binding are known as canonical IRS signaling pathways (1,3,11,24,25 2) IRSs in mammary gland development and function 2.1) IRS levels during postnatal developmentA number of studies have shown the significance of the IGF system in mammary gland development (for review see other articles in this journal). We showed that IRS-1 and IRS-2 proteins are expressed in all stages of mammary gland development (39). In nulliparous mice, both proteins are expressed in epithelial ducts and terminal end buds (TEBs), and only rarely myoepithelium or stroma. Interestingly, we found that IRS-1 expression showed a unique punctuate pattern in t...

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Section: ) Irss In Human Breast Cancermentioning

confidence: 99%

Insulin Receptor Substrates (IRSs) and Breast Tumorigenesis

Chan

Lee

2008

J Mammary Gland Biol Neoplasia

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“…For example, the Pro12Ala variant of the peroxisome proliferator-activated receptor gamma ( PPARG ) gene may influence SHBG level (26). The Gly972Arg variant in the insulin receptor substrate-1 gene ( IRS1 ) was associated with decreased circulating SHBG in post-menopausal breast cancer survivors (27). In addition to PPARG and IRS1, HMGCR may belong to this cluster of genes which can provide a genetic link between insulin resistance/sensitivity and SHBG level, although the molecular mechanism of how HMGCR variants influence SHBG level is not currently known.…”

Section: Discussionmentioning

confidence: 99%

Variants in the HMG-CoA reductase (HMGCR) gene influence component phenotypes in polycystic ovary syndrome

Taylor

Azziz

et al. 2010

Fertility and Sterility

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Objective-To study the role of genetic variation in the HMG-CoA reductase (HMGCR) gene in PCOS.Design-Women with and without PCOS were genotyped for seven single nucleotide polymorphisms (SNPs) in HMGCR. SNPs and haplotypes were determined and tested for association with PCOS and its component traits.Setting-Subjects were recruited from the reproductive endocrinology clinic at the University of Alabama at Birmingham; controls were recruited from the surrounding community. Genotyping took place at Cedars-Sinai Medical Center in Los Angeles.Patient(s)-A total of 287 white PCOS women and 187 controls were studied. Intervention(s)-Phenotypic and genotypic assessment. Main outcome measure(s)-HMGCR genotype, PCOS diagnosis, androgen levels, metabolic traits.Result(s)-No association with PCOS was observed. SNP rs4629571 was associated with increased HOMA-IR. Haplotype 3 was associated with increased HOMA-IR; Haplotype 5 was associated with higher sex hormone binding globulin (SHBG) and lower free testosterone. Conclusion-Variation in the HMGCRgene may influence component features of PCOS including insulin resistance, SHBG, and free testosterone. HMGCR may thus act as a modifier gene in PCOS.

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“…5, 6 There is growing evidence that genetic factors may also affect the incidence and/or aggressiveness of BC in African American women. 7–10 Socioeconomic factors have also been shown to play a role in creating this disparity, e.g., lack of insurance coverage, 11, 12 reduced access to screening 13 and treatment, 14–16 and treatment differences. 15, 17, 18 …”

Section: Introductionmentioning

confidence: 99%

A Cluster Randomized Controlled Trial to Increase Breast Cancer Screening Among African American Women: The Black Cosmetologists Promoting Health Program

Sadler

et al. 2011

Journal of the National Medical Association

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Background African American women have disproportionately higher rates of breast cancer (BC) mortality than all other ethnic groups, thus highlighting the importance of promoting early detection. Methods African American women (N = 984) from San Diego, California participated in a randomized controlled trial testing the efficacy of BC education sessions offered in beauty salons. Cosmetologists received ongoing support, training, and additional culturally aligned educational materials to help them engage their clients in dialogues about the importance of BC early detection. Posters and literature about BC early detection were displayed throughout the salons and cosmetologists used synthetic breast models to show their clients how BC lumps might feel. Participants in the control group received a comparable diabetes education program. Baseline and six month follow-up surveys were administered to evaluate changes in women’s BC knowledge, attitudes and screening behaviors. Results This intervention was well received by the participants and their cosmetologists and did not interfere with, or prolong, the client’s salon visit. Women in the intervention group reported significantly higher rates of mammography compared to women in the control group. Training a single educator proved sufficient to permeate the entire salon with the health message and salon clients agreed that cosmetologists could become effective health educators. Conclusions Cosmetologists are in an ideal position to increase African American women’s BC knowledge and adherence to BC screening guidelines.

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An association between a common variant (G972R) in the IRS-1 gene and sex hormone levels in post-menopausal breast cancer survivors

Cited by 4 publications

References 67 publications

Insulin Receptor Substrates (IRSs) and Breast Tumorigenesis

Insulin Receptor Substrates (IRSs) and Breast Tumorigenesis

Variants in the HMG-CoA reductase (HMGCR) gene influence component phenotypes in polycystic ovary syndrome

A Cluster Randomized Controlled Trial to Increase Breast Cancer Screening Among African American Women: The Black Cosmetologists Promoting Health Program

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