Survival probability based on P53 marker.

A: Disease free survival probability (Kaplan-Meier curve, negative vs. positive, p = 0.002) B: Disease-free survival for hormone therapy (P = 0.005).C: Disease-free survival for chemotherapy (p<0.0001).</p

Association of protein expression with breast cancer progression.

Association of protein expression with breast cancer progression.</p

Survival probability based on joint effect of P53 and p16 expression.

A: Overall survival probability, P53+/P16+ VS. P53-/P16- (p = 0.000), P53+/P16+ vs. P53+/P16- (p = 0.008), P53+/P16- VS. P53-/P16+ (p = 0.049) and P53-/P16+ vs. P53-/P16- (p = 0.000) showed significant differences on overall survival. The worst outcome was seen in patients P53+/P16+ tumours.B: Disease free survival, P53+/P16+ VS. P53-/P16- (p = 0.000), P53+/P16+ vs. P53+/P16- (p = 0.017) and P53-/P16+ vs. P53-/P16- (p = 0.000) showed significant differences in DFS. The worst outcome was seen in patients with P53+/P16+ tumours.</p

Association of p14 and P53 status with overall and disease-free survival.

Association of p14 and P53 status with overall and disease-free survival.</p

Univariate and multivariate cox regression to estimate the hazards ratio.

Univariate and multivariate cox regression to estimate the hazards ratio.</p

Association of P53 and p16 status with overall and disease-free survival.

Association of P53 and p16 status with overall and disease-free survival.</p

Association of senescence-associated markers with clinicopathological variables.

Association of senescence-associated markers with clinicopathological variables.</p

Survival probability based on joint effect of P14 and P53 expression.

A: Overall survival, no significant difference was seen between each combination B: Disease free survival probability based on joint effect of P14 and P53 expression. P14+/P53+ VS. P14-/P53- (p = 0.001) and P14+/P53+ vs. P14+/P53- (p = 0.007) showed significant differences in DFS. The worst outcome was seen in patients with P14+/P53+ tumours.</p

LRH-1 expression patterns in breast cancer tissues are associated with tumour aggressiveness

The significance and regulation of liver receptor homologue 1 (LRH-1, NR5A2), a tumour-promoting transcription factor in breast cancer cell lines, is unknown in clinical breast cancers. This study aims to determine LRH-1/NR5A2 expression in breast cancers and relationship with DNA methylation and tumour characteristics. In The Cancer Genome Atlas breast cancer cohort NR5A2 expression was positively associated with intragenic CpG island methylation (1.4-fold expression for fully methylated versus not fully methylated, p=0.01) and inversely associated with promoter CpG island methylation (0.6-fold expression for fully methylated versus not fully methylated, p=0.036). LRH-1 immunohistochemistry of 329 invasive carcinomas and ductal carcinoma in situ (DCIS) was performed. Densely punctate/ coarsely granular nuclear reactivity was significantly associated with high tumour grade (p < 0.005, p=0.033 in invasive carcinomas and DCIS respectively), negative estrogen receptor status (p=0.008, p=0.038 in overall cohort and invasive carcinomas, respectively), negative progesterone receptor status (p=0.003, p=0.013 in overall cohort and invasive carcinomas, respectively), HER2 amplification (overall cohort p=0.034) and non-luminal intrinsic subtype (p=0.018, p=0.038 in overall cohort and invasive carcinomas, respectively). These significant associations of LRH-1 protein expression with tumour phenotype suggest that LRH-1 is an important indicator of tumour biology in breast cancers and may be useful in risk stratification

Myoepithelial cell-specific expression of stefin A as a suppressor of early breast cancer invasion

Mammography screening has increased the detection of early pre-invasive breast cancers, termed ductal carcinoma in situ (DCIS), increasing the urgency of identifying molecular regulators of invasion as prognostic markers to predict local relapse. Using the MMTV-PyMT breast cancer model and pharmacological protease inhibitors, we reveal that cysteine cathepsins have important roles in early-stage tumorigenesis. To characterize the cell-specific roles of cathepsins in early invasion, we developed a DCIS-like model, incorporating an immortalized myoepithelial cell line (N1ME) that restrained tumor cell invasion in 3D culture. Using this model, we identified an important myoepithelial-specific function of the cysteine cathepsin inhibitor stefin A in suppressing invasion, whereby targeted stefin A loss in N1ME cells blocked myoepithelial-induced suppression of breast cancer cell invasion. Enhanced invasion observed in 3D cultures with N1ME stefin A-low cells was reliant on cathepsin B activation, as addition of the small molecule inhibitor CA-074 rescued the DCIS-like non-invasive phenotype. Importantly, we confirmed that stefin A was indeed abundant in myoepithelial cells in breast tissue. Use of a 138-patient cohort confirmed that myoepithelial stefin A (cystatin A) is abundant in normal breast ducts and low-grade DCIS but reduced in high-grade DCIS, supporting myoepithelial stefin A as a candidate marker of lower risk of invasive relapse. We have therefore identified myoepithelial cell stefin A as a suppressor of early tumor invasion and a candidate marker to distinguish patients who are at low risk of developing invasive breast cancer, and can therefore be spared further treatment. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd