Abstract 4250: Molecular alterations in the breast associated with early menarche

Background: Menarche, the onset of the female menstruation, is a marker of pubertal timing. Age at menarche varies widely between girls and is highly dependent on nutritional status and body fat accumulation. The occurrence of menarche at an early age is linked to an increased risk of several adverse health conditions later in life, such as obesity, type-2 diabetes, breast and endometrial cancer, and cardiovascular disease. Indeed, for every one year decrease in age at menarche (from an average age at menarche of 12.5 years), breast cancer risk is increased by 5%. Several genome wide association studies (GWAS) have identified genetic variants (i.e. in the LIN28B gene) that are associated with early age at menarche, however little is known about the changes occurring in the breast tissue of women with early menarche. We hypothesize that early age at menarche results in permanent molecular alterations in the breast tissue and that those abnormalities may contribute to the tissue’s susceptibility to carcinogens and breast cancer development. Methods: To test our hypothesis we used the resources available at the Susan G. Komen Tissue Bank at the Indiana University Simon Cancer Center (KTB). We selected histologically normal breast tissue from healthy, young women with either early (age ≤ 10 years) or late menarche (age ≥ 15 years), and matched for age, race, BMI, and menstrual phase. Breast tissue biopsies from these women were microdissected to isolate the breast epithelium and next generation RNA-sequencing was used to generate a transcriptome profile for each sample. Differential expression was performed using DESeq2 in R. The tissue samples were also evaluated using immunostaining. Results/Conclusions: Preliminary data show significant differences when comparing the transcriptome profiles of the microdissected breast epithelium from the early and late menarche sample cohorts. The tissue from women with early menarche had upregulation of genes associated with defense against oxidative stress and/or infectious bacteria (lactotransferrin [LTF], ceruloplasmin [CP]), cell adhesion, (ITGα11, ITGαX, ITGαM, ITGαL, ITGβ2), immune response (CARD9, LAIR1), and had downregulation of ubiquitination pathways (USP40, AMFR) and lipoprotein metabolism (OSBPL1A, LIPH, PIGN). Immunohistochemical evaluation of markers of oxidative stress (LTF, CP), cell proliferation (Ki67), and immune infiltrates (CD45, CD20, CD8, CD68) is underway. Together, this information will give us the opportunity to better understand early age at menarche as a breast cancer risk factor and advance research for women’s health. Citation Format: Mariah L. Johnson, Natascia Marino, Anna Maria V. Storniolo, Bradley A. Hancock, Milan Radovich, George E. Sandusky. Molecular alterations in the breast associated with early menarche [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4250. doi:10.1158/1538-7445.AM2017-4250