Evolutionary Pathways in BRCA1-Associated Breast Tumors

Abstract

BRCA1-associated breast tumors display loss of BRCA1 and frequent somatic mutations of PTEN and TP53. Here we describe the analysis of BRCA1, PTEN, and p53 at the single cell level in 55 BRCA1-associated breast tumors and computational methods to predict the relative temporal order of somatic events, on the basis of the frequency of cells with single or combined alterations. Although there is no obligatory order of events, we found that loss of PTEN is the most common first event and is associated with basal-like subtype, whereas in the majority of luminal tumors, mutation of TP53 occurs first and mutant PIK3CA is rarely detected. We also observed intratumor heterogeneity for the loss of wild-type BRCA1 and increased cell proliferation and centrosome amplification in the normal breast epithelium of BRCA1 mutation carriers. Our results have important implications for the design of chemopreventive and therapeutic interventions in this high-risk patient population. SIGNIFICANCE Defining the temporal order of tumor-driving somatic events is critical for early detection, risk stratification, and the design of chemopreventive therapies. Our combined experimental and computational approach reveal that the loss of wild-type BRCA1 may not be the first event in the majority of BRCA1-associated breast tumors and may not be present in all cancer cells within tumors.

Progesterone Receptor A Stability Is Mediated by Glycogen Synthase Kinase-3β in the Brca1-deficient Mammary Gland

“…These observations indicated that BRCA1 serves as a negative regulator for PRs (11). Similarly, increased PR expression and proliferation were reported in the normal breast epithelium of BRCA1 mutation carriers (17). BRCA1 contains E3 ubiquitin ligase at its amino-terminal region, which may directly dictate the stability of PR-A.…”

Palb2 synergizes with Trp53 to suppress mammary tumor formation in a model of inherited breast cancer

“…For example, the tumors in this mouse model driven by K14-Cre were uniformly of the triple negative phenotype. This characteristic might well contribute to the absence of haploinsufficiency in our system, in the same way that BRCA1 mammary tumors derived from distinct cell populations display preferential patterns of consecutive LOH events along the tumorigenesis pathway (32,51).…”

Association between Basal-Like Phenotype and BRCA1/2 Germline Mutations in Korean Breast Cancer Patients

“…Several studies have reported that loss of pten expression is significantly associated with basal-like breast cancer and BRCA1-associated hereditary breast cancer 13,15 . Phuah et al 17 evaluated pten status for 26 tnbc patients and reported that the addition of 2 criteria (triple negativity and pten status) improved the sensitivity of the Manchester scoring method, suggesting that pten status could improve the identification of BRCA1 mutation carriers.…”

“…Both are also characterized by overexpression of egfr (epidermal growth factor receptor) and basal cytokeratins, and by negativity for phosphate and tensin homologue (pten), which are considered to be predictors for BRCA1 mutation 8,[12][13][14][15] .…”