Chemotherapy-induced monoamine oxidase expression in prostate carcinoma functions as a cytoprotective resistance enzyme and associates with clinical outcomes.

To identify molecular alterations in prostate cancers associating with relapse following neoadjuvant chemotherapy and radical prostatectomy patients with high-risk localized prostate cancer were enrolled into a phase I-II clinical trial of neoadjuvant chemotherapy with docetaxel and mitoxantrone followed by prostatectomy. Pre-treatment prostate tissue was acquired by needle biopsy and post-treatment tissue was acquired by prostatectomy. Prostate cancer gene expression measurements were determined in 31 patients who completed 4 cycles of neoadjuvant chemotherapy.

PPP2R2C loss promotes castration-resistance and is associated with increased prostate cancer-specific mortality.

Metastatic prostate cancers generally rely on androgen receptor (AR) signaling for growth and survival, even following systemic androgen-deprivation therapy (ADT). However, recent evidence suggests that some advanced prostate cancers escape ADT by using signaling programs and growth factors that bypass canonical AR ligand-mediated mechanisms. We used an in vitro high-throughput RNA interference (RNAi) screen to identify pathways in androgen-dependent prostate cancer cell lines whose loss-of-function promotes androgen ligand-independent growth.

Prognostic value of ERG oncoprotein in prostate cancer recurrence and cause-specific mortality.

Background: ETS-related gene (ERG) protein is present in 40-70% of prostate cancer and is correlated with TMPRSS2-ERG gene rearrangements. This study evaluated ERG expression at radical prostatectomy to determine whether it was predictive of earlier relapse or prostate cancer-specific mortality (PCSM).

Methods: One hundred patients who underwent radical prostatectomy at Virginia Mason in Seattle between 1991 and 1997 were identified.

Epistatic Control of Mammary Cancer Susceptibility in Mice may Depend on the Dietary Environment.

Recent studies have linked a high fat diet to the development of breast cancer, but any genetic basis for this association is poorly understood. We investigated this association with an epistatic analysis of seven cancer traits in a segregating population of mice with metastatic mammary cancer that were fed either a control or a high-fat diet. We used an interval mapping approach with single nucleotide polymorphisms to scan all 19 autosomes, and discovered a number of diet-independent epistatic interactions of quantitative trait loci (QTLs) affecting these traits.

Cellular senescence and cancer chemotherapy resistance.

Innate or acquired resistance to cancer therapeutics remains an important area of biomedical investigation that has clear ramifications for improving cancer specific death rates. Importantly, clues to key resistance mechanisms may lie in the well-orchestrated and highly conserved cellular and systemic responses to injury and stress. Many anti-neoplastic therapies typically rely on DNA damage, which engages potent DNA damage response signaling pathways that culminate in apoptosis or growth arrest at checkpoints to allow for damage repair.

Sex-, diet-, and cancer-dependent epistatic effects on complex traits in mice.

The genetic basis of quantitative traits such as body weight and obesity is complex, with several hundred quantitative trait loci (QTLs) known to affect these and related traits in humans and mice. It also has become increasingly evident that the single-locus effects of these QTLs vary considerably depending on factors such as the sex of the individuals and their dietary environment, and we were interested to know whether this context-dependency also applies to two-locus epistatic effects of QTLs as well. We therefore conducted a genome scan to search for epistatic effects on 13 different weight and adiposity traits in an F(2) population of mice (created from an original intercross of the FVB strain with M16i, a polygenic obesity model) that were fed either a control or a high-fat diet and half of which harbored a transgene (PyMT) that caused the development of metastatic mammary cancer.

Dietary fat-dependent transcriptional architecture and copy number alterations associated with modifiers of mammary cancer metastasis.

Breast cancer is a complex disease resulting from a combination of genetic and environmental factors. Among environmental factors, body composition and intake of specific dietary components like total fat are associated with increased incidence of breast cancer and metastasis. We previously showed that mice fed a high-fat diet have shorter mammary cancer latency, increased tumor growth and more pulmonary metastases than mice fed a standard diet.

Dietary fat alters pulmonary metastasis of mammary cancers through cancer autonomous and non-autonomous changes in gene expression.

Metastasis virulence, a significant contributor to breast cancer prognosis, is influenced by environmental factors like diet. We previously demonstrated in an F2 mouse population generated from a cross between the M16i polygenic obese and MMTV-PyMT mammary cancer models that high fat diet (HFD) decreases mammary cancer latency and increases pulmonary metastases compared to a matched control diet (MCD). Genetic analysis detected eight modifier loci for pulmonary metastasis, and diet significantly interacted with all eight loci.

Parent-of-origin effects on voluntary exercise levels and body composition in mice.

Despite the health-related benefits of exercise, many people do not engage in enough activity to realize the rewards, and little is known regarding the genetic or environmental components that account for this individual variation. We created and phenotyped a large G(4) advanced intercross line originating from reciprocal crosses between mice with genetic propensity for increased voluntary exercise (HR line) and the inbred strain C57BL/6J. G(4) females (compared to males) ran significantly more when provided access to a running wheel and were smaller with a greater percentage of body fat pre- and postwheel access.

Genotype X diet interactions in mice predisposed to mammary cancer: II. Tumors and metastasis.

High dietary fat intake and obesity may increase the risk of susceptibility to certain forms of cancer. To study the interactions of dietary fat, obesity, and metastatic mammary cancer, we created a population of F(2) mice cosegregating obesity QTL and the MMTV-PyMT transgene. We fed the F(2) mice either a very high-fat or a matched-control-fat diet, and we measured growth, body composition, age at mammary tumor onset, tumor number and severity, and formation of pulmonary metastases.

Genotype X diet interactions in mice predisposed to mammary cancer. I. Body weight and fat.

High dietary fat intake and obesity may increase susceptibility to certain forms of cancer. To study the interactions of dietary fat, obesity, and metastatic mammary cancer, we created a population of F(2) mice cosegregating obesity QTL and the MMTV-PyMT transgene. We fed the F(2) mice either a very-high-fat or a matched-control-fat diet and measured growth, body composition, age at mammary tumor onset, tumor number and severity, and formation of pulmonary metastases.