TSHZ2 is an EGF-regulated tumor suppressor that binds to the cytokinesis regulator PRC1 and inhibits metastasis.

Unlike early transcriptional responses to mitogens, later events are less well-characterized. Here, we identified delayed down-regulated genes (DDGs) in mammary cells after prolonged treatment with epidermal growth factor (EGF). The expression of these DDGs was low in mammary tumors and correlated with prognosis. The proteins encoded by several DDGs directly bind to and inactivate oncoproteins and might therefore act as tumor suppressors. The transcription factor teashirt zinc finger homeobox 2 (TSHZ2) is encoded by a DDG, and we found that overexpression of TSHZ2 inhibited tumor growth and metastasis and accelerated mammary gland development in mice. Although the gene TSHZ2 localizes to a locus (20q13.2) that is frequently amplified in breast cancer, we found that hypermethylation of its promoter correlated with down-regulation of TSHZ2 expression in patients. Yeast two-hybrid screens and protein-fragment complementation assays in mammalian cells indicated that TSHZ2 nucleated a multiprotein complex containing PRC1/Ase1, cyclin B1, and additional proteins that regulate cytokinesis. TSHZ2 increased the inhibitory phosphorylation of PRC1, a key driver of mitosis, mediated by cyclin-dependent kinases. Furthermore, similar to the tumor suppressive transcription factor p53, TSHZ2 inhibited transcription from the PRC1 promoter. By recognizing DDGs as a distinct group in the transcriptional response to EGF, our findings uncover a group of tumor suppressors and reveal a role for TSHZ2 in cell cycle regulation.

A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer.

Biallelic inactivation of BRCA1 or BRCA2 is associated with a pattern of genome-wide mutations known as signature 3. By analyzing ∼1,000 breast cancer samples, we confirmed this association and established that germline nonsense and frameshift variants in PALB2, but not in ATM or CHEK2, can also give rise to the same signature. We were able to accurately classify missense BRCA1 or BRCA2 variants known to impair homologous recombination (HR) on the basis of this signature. Finally, we show that epigenetic silencing of RAD51C and BRCA1 by promoter methylation is strongly associated with signature 3 and, in our data set, was highly enriched in basal-like breast cancers in young individuals of African descent.

The association of patient characteristics and surgical variables on symptoms of pain and function over 5 years following primary hip-replacement surgery: a prospective cohort study.

OBJECTIVES: To identify patient characteristics and surgical factors associated with patient-reported outcomes over 5 years following primary total hip replacement (THR). DESIGN: Prospective cohort study. SETTING: Seven hospitals across England and Scotland. PARTICIPANTS: 1431 primary hip replacements for osteoarthritis. MAIN OUTCOME MEASURES: The Oxford Hip Score (OHS) was collected preoperatively and each year up to 5 years postoperatively. Repeated measures such as linear regression modelling are used to identify patient and surgical predictors of outcome and describe trends over time. RESULTS: The majority of patients demonstrated substantial improvement in pain/function in the first year after surgery-between 1 and 5 years follow-up, there was neither further improvement nor decline. The strongest determinant of attained postoperative OHS was the preoperative OHS-those with worse preoperative pain/function had worse postoperative pain/function. Other predictors with small but significant effects included: femoral component offset-women with an offset of 44 or more had better outcomes; age-compared to those aged 50-60, younger (age <50) and older patients (age >60) had worse outcome, increasing body mass index (BMI), more coexisting diseases and worse Short Form 36 mental health (MH) was related to worse postoperative pain/function. Assessment of change in OHS between preoperative  and postoperative assessments revealed that patients achieved substantial and clinically relevant symptomatic improvement (change), regardless of variation in these patient and surgical factors. CONCLUSIONS: Patients received substantial benefit from surgery, regardless of their preoperative assessments and surgical characteristics (baseline pain/function, age, BMI, comorbidities, MH and femoral component offset). Further research is needed to identify other factors that can improve our ability to identify patients at risk of poor outcomes from THR surgery.