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Estrogen dependence is major driver of ER + breast cancer, which is associated with PI3K mutation. PI3K inhibition (PI3Ki) can restore dependence on ER signaling for some hormone therapy-resistant ER + breast cancers, but is ineffective in others. Here we show that short-term supplementation with estrogen strongly enhanced Pik3caH1047R-induced mammary tumorigenesis in mice that resulted exclusively in ER + tumors, demonstrating the cooperation of the hormone and the oncogene in tumor development. Similar to human ER + breast cancers that are endocrine-dependent or endocrine-independent at diagnosis, tumor lines from this model retained ER expression but were sensitive or resistant to hormonal therapies. PI3Ki did not induce cell death but did cause upregulation of the pro-apoptotic gene BIM. BH3 mimetics or PI3Ki were unable to restore hormone sensitivity in several resistant mouse and human tumor lines. Importantly however, combination of PI3Ki and BH3 mimetics had a profound, BIM-dependent cytotoxic effect in PIK3CA-mutant cancer cells while sparing normal cells. We propose that addition of BH3 mimetics offers a therapeutic strategy to markedly improve the cytotoxic activity of PI3Ki in hormonal therapy-resistant and ER-independent PIK3CA-mutant breast cancer.

TP53 is the most commonly mutated tumor suppressor gene and its mutation drives tumorigenesis. Using ChIP-seq for p53 in the absence of acute cell stress, we found that wild-type but not mutant p53 binds and activates numerous tumor suppressor genes, including PTEN, STK11(LKB1), miR-34a, KDM6A(UTX), FOXO1, PHLDA3, and TNFRSF10B through consensus binding sites in enhancers and promoters. Depletion of p53 reduced expression of these target genes, and analysis across 18 tumor types showed that mutation of TP53 associated with reduced expression of many of these genes. Regarding PTEN, p53 activated expression of a luciferase reporter gene containing the p53-consensus site in the PTEN enhancer, and homozygous deletion of this region in cells decreased PTEN expression and increased growth and transformation. These findings show that p53 maintains expression of a team of tumor suppressor genes that may together with the stress-induced targets mediate the ability of p53 to suppress cancer development. p53 mutations selected during tumor initiation and progression, thus, inactivate multiple tumor suppressor genes in parallel, which could account for the high frequency of p53 mutations in cancer. Implications: In this study, we investigate the activities of p53 under normal low-stress conditions and discover that p53 is capable of maintaining the expression of a group of important tumor suppressor genes at baseline, many of which are haploinsufficient, which could contribute to p53-mediated tumor suppression. Mol Cancer Res; 15(8); 1051–62. ©2017 AACR.

Tone, vowel and consonant production are described for a large group of Cantonese-speaking children assessed in speech and language therapy clinics in Hong Kong. The patterns of disability follow predictions made on the basis of work on normal phonological development in Cantonese, and on psychoacoustic factors in acquisition: consonants account for more disability than vowels, and tones are least problematic. Possible articulatory and auditory contributions to explanation of the observed patterns are discussed.

Purpose To report Propionibacterium acnes as a cause of vision-threatening infectious keratitis and to discuss culture isolation and antibiotic treatment. Methods Retrospective case series presentation collected from three academic medical centers. Results Six cases of P. acnes infectious keratitis are presented, all of which were associated with a compromised corneal barrier or environment. All cases were culture-positive on thioglycolate broth; none became positive before 7 days of growth. No other organisms were isolated from any culture, and the growth of P. acnes occurred in some cases despite negative gram stains. Conclusion P. acnes can produce vision-debilitating keratitis when the cornea is compromised. Growth in culture should be monitored for at least 10 days to ensure isolation of this fastidious organism. P. acnes may respond to several different antibiotics that have gram-positive coverage, but it should be treated with vancomycin to enhance clearance of the organism.