Pregnancy Hypertension and a Commonly Inherited IGF1R Variant (rs2016347) Reduce Breast Cancer Risk by Enhancing Mammary Gland Involution

Abstract

Background Terminal duct lobular units (TDLUs) are the anatomic sites of breast cancer initiation, and breast tissue involution resulting in lower TDLU counts has been associated with decreased breast cancer risk. The insulin-like growth factor (IGF) pathway plays a role in breast involution, and systemic changes in this developmental pathway occur with hypertensive disorders of pregnancy (HDP), which have also been associated with lower breast cancer risk, especially in women carrying a functional variant of IGF1R SNP rs2016347. We proposed that this breast cancer protective effect might be explained by increased breast tissue involution. Materials and Methods We conducted a retrospective cohort study utilizing the Komen Tissue Bank, which collects breast tissue core biopsies from women without a history of breast cancer. Eighty white non-Hispanic women with a history of HDP were selected along with 120 nonexposed participants, and after genotyping for rs2016347, TDLU parameters were histologically measured blinded to participant characteristics from fixed biopsy sections. Results Stratified models by HDP status demonstrated that among HDP+ participants, those carrying two T alleles of rs2016347 had a decrease in TDLU counts of 53.2% when compared to those with no T alleles (p=0.049). Trend analysis demonstrated a multiplicative decrease in counts of 31.6% per T allele (p=0.050). Although no statistically significant interaction was seen between HDP status and T alleles, interaction terms showed increasingly negative values reaching a p value of 0.124 for HDP × 2T alleles. Conclusions The observed statistically significant decrease in TDLU counts signifies increased breast epithelial involution in women with prior HDP who inherited the TT genotype of IGF1R SNP rs2016347. The increasing degree of breast involution with greater rs2016347 T allele copy number is consistent with the known progressive reduction in IGF1R expression in breast and other normal tissues.

miR‑589‑3p sponged by the lncRNA TINCR inhibits the proliferation, migration and invasion and promotes the apoptosis of breast cancer cells by suppressing the Akt pathway via IGF1R

“…Turner et al ( 51 ) reported that IGF1R expression is increased in resected breast cancer tumor tissues and is associated with early recurrence. Powell et al ( 52 ) demonstrated that the commonly inherited IGF1R variant (rs2016347) reduces breast cancer risk by enhancing mammary gland involution. In addition, triptolide and IGF1R inhibitor (AG1024) can synergistically inhibit the proliferation and induce the apoptosis of triple-negative breast cancer cells ( 53 ).…”

A risk-associated Active transcriptome phenotype expressed by histologically normal human breast tissue and linked to a pro-tumorigenic adipocyte population

“…This histologic analysis confirmed that no sample contained preneoplastic or neoplastic cells. Furthermore, terminal duct lobular unit (TDLU) counts were independently and blindly determined on each H&E slide as recently reported [ 7 ]. For adipocyte cross-sectional area assessment, four representative images from each H&E slide were analyzed at × 50 magnification (measuring ≥ 50 adipocytes per image) using Fiji imaging software with the open-source Adiposoft v1.13 plugin, as previously described [ 8 ].…”

A common IGF1R gene variant predicts later life breast cancer risk in women with preeclampsia

“…Similarly, elevated serum levels or increased expression of IGF-1 has been implicated in the development of various non-breast cancers [ 31 – 35 ]. Of mechanistic relevance to the present study, the normal breast tissue of women with a history of preeclampsia who also inherit the lower expressing T allele of IGF1R rs2016347 exhibits increased mammary gland involution, a histologic predictor of reduced breast cancer risk [ 36 ].…”