PTEN loss and activation of K-RAS and ß-catenin cooperate to accelerate prostate tumourigenesis.

Aberrant phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinase (MAPK) and WNT signalling are emerging as key events in the multistep nature of prostate tumourigenesis and progression. Here, we report a compound prostate cancer murine model in which these signalling pathways cooperate to produce a more aggressive prostate cancer phenotype. Using Cre-LoxP technology and the probasin promoter, we combined the loss of Pten (Ptenfl/fl ), to activate the PI3K signalling pathway, with either dominant stabilized ß-catenin [Catnb+/lox(ex3) ] or activated K-RAS (K-Ras+/V12 ) to aberrantly activate WNT and MAPK signalling, respectively. Synchronous activation of all three pathways (triple mutants) significantly reduced survival (median 96 days) as compared with double mutants [median: 140 days for Catnb+/lox(ex3) Ptenfl/fl ; 182 days for Catnb+/lox(ex3) K-Ras+/V12 ; 238 days for Ptenfl/fl K-Ras+/V12 ], and single mutants [median: 383 days for Catnb+/lox(ex3) ; 407 days for Ptenfl/fl ], reflecting the accelerated tumourigenesis. Tumours followed a stepwise progression from mouse prostate intraepithelial neoplasia to invasive adenocarcinoma, similar to that seen in human disease. There was significantly elevated cellular proliferation, tumour growth and percentage of invasive adenocarcinoma in triple mutants as compared with double mutants and single mutants. Triple mutants showed not only activated AKT, extracellular-signal regulated kinase 1/2, and nuclear ß-catenin, but also significantly elevated signalling through mechanistic target of rapamycin complex 1 (mTORC1). In summary, we show that combined deregulation of the PI3K, MAPK and WNT signalling pathways drives rapid progression of prostate tumourigenesis, and that deregulation of all three pathways results in tumours showing aberrant mTORC1 signalling. As mTORC1 signalling is emerging as a key driver of androgen deprivation therapy resistance, our findings are important for understanding the biology of therapy-resistant prostate cancer and identifying potential approaches to overcome this. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Radial scar lesions of the breast diagnosed by needle core biopsy: analysis of cases containing occult malignancy.

AIM: To identify and review cases of false negative needle core biopsy (NCB) in the preoperative investigation of radial scar/complex sclerosing lesion (RS/CSL) lesions - that is, benign NCB from RS/CSL which contained malignancy on excision. METHODS AND RESULTS: A total of 11 false negative NCB in RS/CSL lesions from 281 (3.9%) were identified (6 cases: B1, 2 cases: B2 and 3 cases: B3). In 6 of 11 cases a radial scar or stromal sclerosis was seen in NCB. Localisation biopsy showed duct carcinoma in situ in six cases, duct carcinoma in situ with invasive carcinoma in three and invasive carcinoma in two. In all 11 cases, needle tracks were identified as missing the malignant epithelium by a mean of 5 mm (median:4 mm; range:1-20 mm). In 9 of 11 cases, the malignancy was missed by <6 mm. CONCLUSIONS: Despite evidence of accurate targeting of lesions, the use of NCB instead of fine needle aspiration cytology has not eliminated the problem of false negative biopsy in RS/CSL, and excision is recommended.