Purpose Type 2 diabetes (T2D) has been reported to be associated with an elevated risk of breast cancer. It is unclear, however, whether this association is due to shared genetic factors. Methods We constructed a genetic risk score (GRS) using risk variants from 33 known independent T2D susceptibility loci and evaluated its relation to breast cancer risk using the data from two consortia, including 62,328 breast cancer patients and 83,817 controls of European ancestry. Unconditional logistic regression models were used to derive adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) to measure the association of breast cancer risk with T2D GRS or T2D-associated genetic risk variants. Meta-analyses were conducted to obtain summary ORs across all studies. Results The T2D GRS was not found to be associated with breast cancer risk, overall, by menopausal status, or for estrogen receptor positive or negative breast cancer. Three T2D associated risk variants were individually associated with breast cancer risk after adjustment for multiple comparisons using the Bonferroni method (at p < 0.001), rs9939609 (FTO) (OR 0.94, 95 % CI = 0.92–0.95, p = 4.13E−13), rs7903146 (TCF7L2) (OR 1.04, 95 % CI = 1.02–1.06, p = 1.26E−05), and rs8042680 (PRC1) (OR 0.97, 95 % CI = 0.95–0.99, p = 8.05E−04). Conclusions We have shown that several genetic risk variants were associated with the risk of both T2D and breast cancer. However, overall genetic susceptibility to T2D may not be related to breast cancer risk.

Genetic variants affecting the regulation of gene expression are among the main causes of human diversity. The potential importance of regulatory polymorphisms is underscored by results from Genome Wide Association Studies, which have already implicated such polymorphisms in the susceptibility to complex diseases such as breast cancer. In this study, we re-sequenced the promoter regions of 24 genes involved in pathways related to breast cancer including sex steroid action, DNA repair, and cell cycle control in 60 unrelated Caucasian individuals. We constructed haplotypes and assessed the functional impact of promoter variants using gene reporter assays and electrophoretic mobility shift assays. We identified putative functional variants within the promoter regions of estrogen receptor 1 (ESR1), ESR2, forkhead box A1 (FOXA1), ubiquitin interaction motif containing 1 (UIMC1) and cell division cycle 7 (CDC7). The functional polymorphism on CDC7, rs13447455, influences CDC7 transcriptional activity in an allele-specific manner and alters DNA–protein complex formation in breast cancer cell lines. Moreover, results from the Breast Cancer Association Consortium show a marginal association between rs13447455 and breast cancer risk (p = 9.3 × 10⁻⁵), thus warranting further investigation. Furthermore, our study has helped provide methodological solutions to some technical difficulties that were encountered with gene reporter assays, particularly regarding inter-clone variability and statistical consistency.

Rare variants in at least 10 genes, including BRCA1, BRCA2, PALB2, ATM, and CHEK2, are associated with increased risk of breast cancer; however, these variants, in combination with common variants identified through genome-wide association studies, explain only a fraction of the familial aggregation of the disease. To identify further susceptibility genes, we performed a two-stage whole-exome sequencing study. In the discovery stage, samples from 1528 breast cancer cases enriched for breast cancer susceptibility and 3733 geographically matched unaffected controls were sequenced. Using five different filtering and gene prioritization strategies, 198 genes were selected for further validation. These genes, and a panel of 32 known or suspected breast cancer susceptibility genes, were assessed in a validation set of 6211 cases and 6019 controls for their association with risk of breast cancer overall, and by estrogen receptor (ER) disease subtypes, using gene burden tests applied to loss-of-function and rare missense variants. Twenty genes showed nominal evidence of association (p-value < 0.05) with either overall or subtype-specific breast cancer. Our study had the statistical power to detect susceptibility genes with effect sizes similar to ATM, CHEK2, and PALB2, however, it was underpowered to identify genes in which susceptibility variants are rarer or confer smaller effect sizes. Larger sample sizes would be required in order to identify such genes.

MicroRNAs, small endogenous noncoding RNAs, are involved in the regulation of epidermal homeostasis. Among them, miR-203 was the most described and expressed in human epidermis, promoting keratinocyte (KC) differentiation by repressing genes involved in proliferation. To identify other microRNAs involved in this process, the miRNomes of normal human KCs cultured in monolayer (2-dimensional) or in 3-dimensional reconstructed skin were compared. Besides miR-203, miR-141 was one of the most expressed microRNAs in 3-dimensional culture and was overexpressed in 3-dimensional versus 2-dimensional condition, that is, during KC differentiation. Functional experiments revealed that, mostly expressed in the basal layer, miR-141 decreased KC proliferation and clonogenicity while promoting differentiation. Target prediction algorithm coupled with transcriptomic data of KCs overexpressing miR-141 as well as 3' untranslated region luciferase assays highlighted CCND2 mRNA as a direct target of miR-141, leading to its downregulation by miR-141 overexpression. Finally, CCND2 silencing decreased KC proliferation and induced differentiation, revealing that miR-141 action was mediated by CCND2. MiR-141 features were also compared with those of miR-203 in parallel experiments. Although miR-141 displayed functions similar to those of miR-203, it exhibited different localization and targets, suggesting a joint participation of miR-141 and miR-203 in engaging and maintaining KC toward differentiation, respectively.