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.
Highlights
Terminal duct lobular units (TDLUs) are the main structures within the breast that produce milk and are recognized as the anatomic site of development of most breast cancers [1]
Longitudinal data have shown that women whose breast tissue demonstrates slower involution over time have increased breast cancer risk [5]. e insulin-like growth factor (IGF) pathway has been implicated in playing a role in the involution process, and decreased levels of IGF-1 and increased levels of one of its binding proteins, IGFBP3, have been associated with lower TDLU counts [6,7,8]
hypertensive disorders of pregnancy (HDP) include gestational hypertension and preeclampsia. ese pregnancies are characterized by inadequate cytotrophoblastic invasion of the myometrium and impaired transformation of the spiral arteries resulting in placental ischemia [9, 10] and alterations in many hormones and growth factors including lower levels of IGF-1 and increased levels of IGFBP3 [11,12,13,14,15]
Summary
Terminal duct lobular units (TDLUs) are the main structures within the breast that produce milk and are recognized as the anatomic site of development of most breast cancers [1]. E 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 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. Conclusions. e 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. e 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
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