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Background: High mobility group A proteins are involved in chromatin remodeling, thereby influencing multiple fundamental biological processes. HMGA2 has been linked to oncogenic traits among a variety of malignancies. Objective: To determine the prognostic implications of subcellular distribution patterns of HMGA2 in breast cancer. Methods: Nuclear and cytoplasmic HMGA2 was evaluated in 342 breast cancer specimens and matched with clinico-pathological parameters. Results: Overall and cytoplasmic, but not nuclear, levels of HMGA2 correlated with better survival prognoses in our collective (hazard ratio (HR) 0.34, P = 0.001 and HR 0.34, P < 0.001, respectively). The protective effect of cytoplasmic HMGA2 persisted in the Luminal A and triple negative breast cancer subgroups. Evaluating Luminal A and B subgroups jointly, only cytoplasmic, but not overall or nuclear HMGA2 levels were associated with better survival (HR 0.42, 95% confidence interval 0.21, 0.86, P = 0.017), irrespective of tumor size and node status. The addition of HMGA2 overall and cytoplasmic scores strengthened the prognostic selectivity in a model of conventional breast cancer risk factors. No predictive significance with regard to endocrine or chemoendocrine therapies was observed. Conclusion: Unexpectedly, we found a favorable survival probability upon overall levels of HMGA2 in our breast cancer collective, which was predominantly determined by the presence of HMGA2 in the cytoplasm.

Pulmonary arterial hypertension is a rare disease that predominantly affects women. The pathophysiology of the disease is complex, with both genetic and hormonal influences. Pregnancy causes significant physiologic changes that may not be well tolerated with underlying pulmonary arterial hypertension, in particular leading to volume overload and increased pulmonary pressures. A multidisciplinary approach and careful monitoring are essential for appropriate management of pulmonary arterial hypertension during pregnancy. Nonetheless, outcomes are still poor, and pregnancy is considered a contraindication in patients with pulmonary arterial hypertension.

Upon ligand binding, plasma membrane-located TNF-related apoptosis-inducing ligand (TRAIL)-receptors 1 and 2 induce apoptosis as well as cancer-promoting signaling in cancer cells. TRAIL-R3 and TRAIL-R4 are believed to negatively regulate TRAIL-mediated apoptosis. Intracellular localization of TRAIL-receptors, as observed in many tumor cells, has been associated with oncogenic features, which are distinct from membrane-associated TRAIL-R signaling. Here, analyzing a panel of 354 breast cancer specimens, we found that an unfavorable outcome correlating with cancer-promoting properties of TRAIL-R1, TRAIL-R2, and TRAIL-R4 was most significantly defined by their intracellular distribution and mutual co-expression. A nuclear or cytoplasmic heterogeneous expression pattern correlated with markedly decreased overall survival and discriminated high-risk breast cancer patients from low-risk patients with a homogeneous distribution of expression, i.e., nuclear and cytoplasmic expression. The homogeneous TRAIL-R expression was associated with favorable breast cancer surrogate markers corresponding with excellent survival prognoses at 5 years after diagnosis (hazard ratio, 0.043) and over the complete course of follow-up (hazard ratio, 0.098; both p 0.001). No associations with specific intrinsic breast cancer subtypes were found. Our data suggest that the determination of intracellular co-expression patterns of TRAIL-R1, TRAIL-R2, and TRAIL-R4 provides an innovative and robust method for risk stratification in breast cancer patients beyond conventional prognostic markers. KEY MESSAGES: A total of 70% of breast cancer specimens show comparably high levels of intracellular TRAIL-Rs. Nuclear or cytoplasmic TRAIL-R co-expression occurs in the majority of tumors. A total of 25% of tumors show a heterogeneous expression of cytoplasmic or nuclear TRAIL-Rs. Patients with a heterogeneous TRAIL-R expression present with poor prognoses. Additive TRAIL-R-based risk stratification comprises different breast cancer subtypes.

Mdm2 (Human mouse double minute 2) is an important opponent of the tumor suppressor p53. The G/G variant of SNP309 in the MDM2 promoter can increase Mdm2 mRNA/protein expression and is associated with an increased risk and earlier onset of different cancers especially in Asian populations. But the frequency and impact of the G/G variant has not been studied in Caucasian renal cell carcinoma (RCC) patients. Therefore, we analyzed an unselected German cohort of 197 consecutive RCC patients and detected the G/G variant in 18 (9.1%) patients, the G/T variant in 116 (58.9%) patients and the T/T variant in 63 (32.0%) patients. Studying the association between age at tumor onset and SNP309 genotypes, no correlation was detected in the entire RCC cohort or among the male RCC patients. However, the female G/G patients (median age 59.5 years) were diagnosed 13.5 years earlier than the T/T females (median age 73 years). Next, when separating all females into two groups at their median age (68 years), 7 patients and 1 patient with the G/G variant and 9 patients and 13 patients with the T/T variant were noted in these age groups (P = 0.024). To study the age dependency of tumor onset further, a second, age-selected cohort of 205 RCC patients was analyzed, which comprised especially young and old patients. Interestingly, the G/G type occurred more often at lower tumor stages and tumor grades compared with higher stages (P = 0.039 and P = 0.004, respectively). In females, the percentage of the G/G variant was only slightly higher in the younger age group, whereas in males, the percentage of the G/G variant was remarkably higher in the younger age group (19.4% vs. 8.0%). In summary, female Caucasian RCC patients with the MDM2 SNP 309 G/G variant showed a significantly earlier tumor onset than patients with the wildtype T/T genotype. Citation Format: Christine G. Stoehr, Robert Stoehr, Antonia Wenners, Arndt Hartmann, Simone Bertz, Verena Spath, Bernhard Walter, Kerstin Junker, Holger Moch, Raoul Hintze, Stefan Denzinger, Elisabeth E. Bond, Gareth L. Bond, Karen Bluemke, Katrin Weigelt, Verena Lieb, Elke Nolte, Paolo Fornara, Bernd Wullich, Sven Wach, Helge W. Taubert. Association of the G/G-SNP309 variant in the mdm2 gene with earlier tumor onset in female renal cell carcinoma patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3700.

Amphiphilic polycations are an alternative to biocides but also toxic to mammalian cells. Antimicrobially active hydrophilic polycations based on 1,4-dibromo-2-butene and tetramethyl-1,3-propanediamine named PBI are not hemotoxic for porcine red blood cells with a hemocytotoxicity (HC50) of more than 40,000 μg · mL(-1). They are quickly killing bacterial cells at their MIC (minimal inhibitory concentration). The highest found selectivity HC50 /MIC is more than 20,000 for S. epidermidis. Investigations on sequentially prepared PBIs with defined molecular weight Mn and tailored end groups revealed that there is a dependence of antimicrobial activity and selectivity on Mn and nature of the end groups.

Background: Sideeffects of adjuvant chemotherapy on ovarian function are inadequately studied by now. Premenopausal women undergoing chemotherapy are at risk for sexual hormone deficiency and impaired fertility. This prospective cohort study searches for predictive parameters of ovarian reserve after chemotherapy. Methods: 51 premenopausal patients (average 38 years; 28-46 years) with primary breast cancer have been included. They all received neo- or adjuvant chemotherapy: anthracycline based "A"(FEC)(n= 18); anthracycline/taxane based "T"( TAC or FEC/Doc or EC/Pac)(n=30) or anthracycline- free "AF"(n=3). After chemotherapy patients received endocrine therapy (ET) for hormone receptor (HR) positive disease (tamoxifen (n=34) or goserelin/tamoxifen (n=7)). For HR negative disease (n=20) no ET was given. Before (visit 1) and 6, 12 and 24 months after initiation of chemotherapy (visit 2-4) age and chemotherapy related changes in hormone (LH, FSH, E2 and Anti-Muellerian hormone (AMH)) levels, antral follicle count and amenorrhea as parameters of endocrine function and fertility were assessed. Also quality of life (QL) and additional impact of parity, BMI and nicotine use on ovarian reserve were evaluated. Results: Antral follicle count is decreasing dramatically after chemotherapy and is not fully recovering after 2 years. Antral follicle count before and 1 year after chemotherapy are significantly correlated (p=0.012). Follicle count and age before chemotherapy are negatively correlated (p=0.004). At visit 4 the type of chemotherapy (A, T, AF) has no influence on antral follicle count or AMH levels. Tamoxifen is correlated with a significant decrease in follicle count (vs. no endocrine therapy) (p=0.039). Smoking is significantly detrimental on antral follicle count after 24 months (p=0.001). AMH levels at visits 2-4 are significantly correlated with levels at the 1 visit and are negatively correlated with age (p=0.032). Tamoxifen therapy has no impact on AMH levels. LH and FSH are increasing between visit 1 and 2 and decreasing at visits 3 and 4 (but stay above basic levels). At visit 4 LH is not and FSH is correlated with visit 1 levels (p=0.005). LH and FSH are correlated with age (p=0.0001) and are not influenced by type of chemotherapy or tamoxifen .E2 levels at visit 4 are not influenced by type of chemotherapy, but significantly decreased (p=0.003) by continued smoking. At visit 4 31/51 patients have stayed amenorrheic, 19 resumed their menstruation. This was not influenced by type of chemotherapy or age. Non- smokers are 13 times more likely to resume their menstruation (vs. smokers). Tamoxifen is correlated with a higher probability of permanent amenorrhea (p=0.058, n.s.). BMI, nicotine abuse, age, type of chemotherapy and tamoxifen have no influence on duration of amenorrhea. QL is significantly lower at visit 2, but recovers to basic values at visits 3 and 4. Conclusions: Our study contributes to a better prediction of ovarian reserve before chemotherapy. We suggest personalized counselling on fertility preserving measures before chemotherapy especially at higher age, with low AMH levels or low antral follicle counts. To stop smoking could enhance chances for ovarian preservation. Citation Format: Christoph Mundhenke, Antonia S Wenners, Jana Grambach, Juliane Koss, Ulrike von Hehn, Walter Jonat, Andreas G Schmutzler. Reduction of ovarian reserve in young early breast cancer patients: 24 months follow up of a prospective cohort trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-12-05.

e19516 Background: Autologous stem cell transplantation (ASCT) followed by maintenance therapy is the standard of care for transplant-eligible patients with newly diagnosed multiple myeloma. Maintenance typically consists of lenalidomide (LEN), however, bortezomib (BOR) and bortezomib-lenalidomide combination are other options. The respective toxicity of these regimens has not been well studied. We performed secondary data analysis to compare incidence of serious adverse events associated with each maintenance therapy group during post-ASCT maintenance treatment period. Methods: Data was extracted from the open-access MMRF Researcher Gateway corresponding with interim analysis from the CoMMpass study. We extracted data of first-time autologous stem cell transplant patients who completed maintenance therapy post-ASCT. We categorized patients into three sub groups bortezomib, lenalidomide or combination (bortezomib and lenalidomide) maintenance therapy. Incidence rate for serious adverse events (grade 3 or higher) was calculated by number of events per 100 person-months for each maintenance therapy. Results: 231 patients were eligible for our analysis. 169 patients received lenalidomide, 27 bortezomib and 35 combination. The most common adverse event was neutropenia and second most common is pneumonia. Neutropenia incidence was 1.1,0.7 and 0.9 per 100 person-months in lenalidomide, bortezomib and combination regimens respectively. Incidence of deep vein thrombosis, GI intolerance and peripheral neuropathy 0.1 per 100 person-months respectively was observed in lenalidomide group only. Combination maintenance had the highest total adverse event incidence rate of 5.4 per 100 person-months. Incidence of 1.7 and 3.8 per 100 person-months is observed in bortezomib and lenalidomide cohorts respectively. Conclusions: Lenalidomide and bortezomib maintenance had similar incidence of serious adverse events. A higher incidence of serious adverse events was noted in the combination lenalidomide/bortezomib regimens. Interestingly, we observed lower incidence of adverse events in all groups in CoMMpass study compared to respective clinical trials involving maintenance regimens. This may be due to under reporting of adverse events in CoMMpass study. The incidence of adverse events mentioned above should be interpreted in the context of drugs and other factors involved in the disease.

Aberrations of chromosome arm 19p in ovarian cancer were first described decades ago and have been confirmed in recent publications, which have focused on chromosome 11 as a translocation partner. Recently, genetic analysis of the ovarian cancer cell line SKOV3 revealed a rearrangement described as der(19)t(11;19)(q13.2;p13.2), which lead to a fusion protein containing parts of HOOK2 and frame shifted ACTN3 that had unknown functionality. To evaluate the frequency of these breakpoints, we used fluorescence in situ hybridization (FISH) probes flanking these genes for interphase analysis of ovarian cancer cells. We analyzed 49 primary cell cultures of ovarian cancers using FISH probes next to these breakpoints on chromosomes 11 and 19 defined in SKOV3. Co-localizations of the signals in interphase nuclei were considered to be positive fusions when the frequency was over the experimentally calculated cutoff of 24.3% (mean average value for normal ovary cells plus three times the standard deviation). Fusions between 11q13.2 and 19p13.2 were confirmed in 22 (45%) primary cell cultures of ovarian cancers. However, by PCR, the fusion originally described in SKOV3 was not detected in any of the primary cell cultures. Our results confirm other reports and show that these regions are very frequently involved in chromosomal rearrangements in ovarian cancer. Furthermore, they reveal a significant correlation (P = 0.023) of co-localized signals of 11q13.2 and 19p13.2 with low and intermediate grades in ovarian cancer.

Background: Imatinib is a tyrosine kinase inhibitor of BCR-ABL, ABL, PDGFR-α and -β, KIT, and DDR. In solid tumors, it inhibits proliferation and invasiveness and facilitates higher intratumoral cytotoxic drug concentrations. Vinorelbine has good tolerability and efficacy in metastatic breast cancer (MBC). This study evaluates the safety and efficacy of imatinib and vinorelbine in combination. Methods: In a prospective, open-label, phase I/II trial, 400 mg imatinib p.o. daily (corrected from 600 mg) was combined with an escalating dose of vinorelbine i.v. weekly in four dose levels of 10, 15, 20, and 25 mg/m2 (each n ≥ 5) to treat patients with MBC (expressing PDGFR-α and/or -β, and/or KIT). The last patient of each level was treated for >28 days, before enrolment for the next dose level started. Study endpoints were feasibility and tolerability, incidence of hematological and nonhematological toxicity, and clinical efficacy (data cutoff: November 18, 2011). A total of 33 patients have been enrolled, and all dose levels have been fully recruited. One patient is still on study medication. A translational subprotocol is ongoing. Results: All 33 included patients are evaluable for safety (32 within the ITT population). Eleven patients were excluded early from the study (progressive disease, toxicity, and withdrawal of consent). Twenty-two patients participated in the study for >28 days (‘ITT >28'). Within the ITT population, the response rate [complete response (CR) and partial response (PR)] was 9.4% (n = 3), the clinical benefit rate (CBR; CR+PR+stable disease) 50% (n = 16), and the median time to progression (TTP) 155 days. A total of 21.3% of the patients were on study medication for >6 months, and 15.2% for >12 months (mean 140 days, range 15-643). Within ‘ITT >28', the response rate was 13.6%, CBR 72.7%, and median TTP 176 days. The response was independent of the receptor status (PDGFR-α, -β, and KIT). Toxicities were as follows (safety population): 21.6% severe leukopenia, 9.1% severe neutropenia (with 1 febrile neutropenia), 1 case of bowel perforation, 36% diarrhea (3% severe), 84.8% nausea (severe 15.2%), 48.5% vomiting (severe 9.1%), 27.3% infections (severe 6.1%), 12.1% peripheral neuropathy (severe 9.1%), and 36.4% dyspnea (3% severe). Four patients on trial died (nondrug-related). Conclusion: The combination of imatinib and vinorelbine in MBC appeared to be feasible and tolerable. A CBR of 50% (ITT) in pretreated patients suggests that this combination may be active. Although toxicities were frequent, they appeared to be manageable.

Studies that use direct observation to investigate drivers’ cell phone use have been conducted by NHTSA since 2002. The limitations of these studies were identified in a naturalistic driving study conducted at the University of Michigan. In direct observation studies of drivers’ cell phone use, observations are typically conducted at intersections, providing the observer with enough time to accurately observe the behavior but limiting data to one location along the roadway. This may be a limitation of large-scale observation usage studies, which, in turn, translates into a research hypothesis that when stopped at intersections, drivers use their cell phones more frequently. Through a combination of in-field observers and video data collection, more than 3,500 vehicles were observed to determine the difference in cell phone use between drivers upstream and those at the intersection. Signalized intersections were found to have a higher rate of text messaging cell phone use, with the highest percentage observed at red lights. Drivers’ text messaging rates increase with the amount of time spent in stopped conditions, such as red lights. The presence of an observer was also found to have an insignificant impact on drivers’ cell phone use. Effective observation of drivers’ cell phone use is essential for understanding the magnitude of the problem and measuring the effectiveness of campaigns. This study confirms the current methods used while providing recommendations on ways to improve the data quality of future observations.

Questionnaire, designed for this study, containing questions on age, marital status, parity and children, education, pre-existing medical conditions, medication, smoking and alcohol consumption, the ongoing desire to have children, history of miscarriage and abortions, contraceptive methods used, the duration of the menstrual cycle, age at menarche, and when amenorrhea occurred during or after chemotherapy. (DOCX 16Â kb)

This report details the 2012 observational study used to determine drivers’ cell phone use in Massachusetts; the study was completed as a component of the annual seat belt observation study by the University of Massachusetts Traffic Safety Research Program. This study identified the magnitude of risky driving behavior throughout Massachusetts. The location, the time of day, and the direction of travel for each observation were determined by random selection with consideration given to the region's fatality rate and length of roadway. Throughout the state, the drivers’ cell phone use at any given daylight hour was determined; the timing allowed for comparisons between different populations. The apparent cell phone use of 17,677 drivers was observed at 145 locations, with a finding of an average cell phone use of 7.0%, a handheld use of 5.6%, and a text messaging use of 1.4%. Females were observed having handheld conversations at a greater rate than males, but there was little difference in text messaging use. Teens were observed text messaging more often than adults and elders, while the handheld conversation rate was similar for teens and adults. Drivers observed wearing seat belts had a lower cell phone use than those who were not wearing seat belts, for text messaging and handheld conversations. Notable variations in cell phone use were identified across various driver demographics, road types, and times of observation and furthered the understanding of drivers’ cell phone use and providing an opportunity for targeted countermeasures.

Background and Objective Progress in endoscopic surgery in the past few decades has led to the application of 3-dimensional (3D) procedures in operating rooms. This permits patient- and surgeon-friendly operations and also maximizes the superiority of laparoscopy over laparotomy. In this study, we compare 2-dimensional (2D) and 3D endoscopy techniques with regard to time, efficiency, optics, and handling by users with different degrees of experience at 4 difficulty levels. Design A randomized controlled trial on a pelvitrainer in objectively graded surgical steps for students and postgraduates. Setting The trials took place at the Kiel School of Gynaecological Endoscopy, a training unit of the Kiel University Department of Obstetrics and Gynecology, a tertiary academic medical center. Participants The 277 study participants, divided into students, residents, and specialists, worked on pelvitrainers with 2 different optical systems, the 2D full HD and the 3D mode. The following 4 exercises were performed with each optical system: (1) grasping and transferring of pins, (2) cutting predetermined marks, (3) vaginal closure with prevention of prolapse, and (4) sacrocolpopexy. The duration and success of the tasks were measured and compared. A self-assessment questionnaire was completed by the participants. Results Overall, the 3D-system permitted a greater improvement in working speed, superior optical visualization, and better endoscopic handling in all groups, independent of surgical experience. All students improved in speed (exercises: 1-3) and made significantly fewer mistakes (exercise 2) on 3D compared with 2D. Residents made progress in time (exercises: 1-4) and task performance (exercise 3). Specialists improved significantly in the more challenging tasks 3 and 4. Subjectively, 68.8% of participants preferred 3D for performing laparoscopy. Conclusion Systematic training programs on pelvitrainers can improve endoscopic skills not only in beginners but also in experienced surgeons. The 3D system offered distinct advantages over 2D imaging and was well accepted by surgeons.

et al., The orphan G protein-coupled receptor GPR55 has been directly or indirectly related to basic alterations that drive malignant growth: uncontrolled cancer cell proliferation, sustained angiogenesis, and cancer cell adhesion and migration. However, little is known about the involvement of this receptor in metastasis. Here, we show that elevated GPR55 expression in human tumors is associated with the aggressive basal/triple-negative breast cancer population, higher probability to develop metastases, and therefore poor patient prognosis. Activation of GPR55 by its proposed endogenous ligand lysophosphatidylinositol confers pro-invasive features on breast cancer cells both in vitro and in vivo. Specifically, this effect is elicited by coupling to G heterotrimeric proteins and the subsequent activation, through ERK, of the transcription factor ETV4/PEA3. Together, these data show that GPR55 promotes breast cancer metastasis, and supports the notion that this orphan receptor may constitute a new therapeutic target and potential biomarker in the highly aggressive triple-negative subtype., This work was supported by grants from Spanish Ministry of Economy and Competitiveness [PI11/00295 to CS, PI14/01101 to CS and EP-G, SAF2013-46183-R to MQ, and SAF2014-54705-R to MV-M, supported with European Regional Development (FEDER) funds] and Madrid Regional Government (S2010/BMD-2308 to MG, and 2010/ BMD-2359 to MQ). EPG was a recipient of a Postdoctoral Research Contract from Fundación Científica Asociación Española Contra el Cáncer and a Federation of the Societies of Biochemistry and Molecular Biology (FEBS) Short-term Fellowship. SB-B and SC-L are recipients of a Formación de Profesorado Universitario (FPU) fellowship and a Ramón y Cajal research contract, respectively, from the Spanish Ministry of Economy and Competitiveness.

Mdm2 (Human mouse double minute 2) ist ein wichtiger Gegenspieler des Tumor suppressors p53. Das Vorliegen der G/G Variante des Einzelnukleotid-polymorphismus 309 (SNP309) im MDM2-Genpromoter kann die Expression von Mdm2 mRNA/Protein stark erhöhen und ist in verschiedenen Tumoren mit [zum vollständigen Text gelangen Sie über die oben angegebene URL], 42. Gemeinsame Tagung der Bayerischen Urologenvereinigung und der Österreichischen Gesellschaft für Urologie und Andrologie

Recombinant adenovirus-engineered dendritic cells (Ad.DC) are potent vaccines for induction of anti-viral and anti-cancer T cell immunity. The effectiveness of Ad.DC vaccines may depend on the newly described ability of Ad.DC to crosstalk with natural killer (NK) cells via cell-to-cell contact, and to mediate activation, polarization and bridging of innate and adaptive immunity. For this interaction to occur in vivo, Ad.DC must be able to attract NK cells from surrounding tissues or peripheral blood. We developed a novel live mouse imaging system-based NK-cell migration test, and demonstrated for the first time that human Ad.DC induced directional migration of human NK cells across subcutaneous tissues, indicating that Ad.DC-NK cell contact and interaction could occur in vivo. We examined the mechanism of Ad.DC-induced migration of NK cells in vitro and in vivo. Ad.DC produced multiple chemokines previously reported to recruit NK cells, including immunoregulatory CXCL10/IP-10 and proinflammatory CXCL8/IL-8. In vitro chemotaxis experiments utilizing neutralizing antibodies and recombinant human chemokines showed that CXCL10/IP-10 and CXCL8/IL-8 were critical for Ad.DC-mediated recruitment of CD56(hi)CD16(-) and CD56(lo)CD16(+) NK cells, respectively. The importance of CXCL8/IL-8 was further demonstrated in vivo. Pretreatment of mice with the neutralizing anti-CXCL8/IL-8 antibody led to significant inhibition of Ad.DC-induced migration of NK cells in vivo. These data show that Ad.DC can recruit spatially distant NK cells toward a vaccine site via specific chemokines. Therefore, an Ad.DC vaccine can likely induce interaction with endogenous NK cells via transmembrane mediators, and consequently mediate Th1 polarization and amplification of immune functions in vivo.

Patients with end-stage heart failure may be treated with home inotropes, “palliatively” or as bridge to left ventricular assist device (LVAD) or transplant (“bridge”). Prior studies showed that home inotropes increased mortality, but were done prior to current medical or device therapy. We

et al., [Background]: Pharmacological activation of cannabinoid receptors elicits antitumoral responses in different cancer models. However, the biological role of these receptors in tumor physio-pathology is still unknown. [Methods]: We analyzed CB2 cannabinoid receptor protein expression in two series of 166 and 483 breast tumor samples operated in the University Hospitals of Kiel, Tübingen, and Freiburg between 1997 and 2010 and CB2 mRNA expression in previously published DNA microarray datasets. The role of CB2 in oncogenesis was studied by generating a mouse line that expresses the human V-Erb-B2 Avian Erythroblastic Leukemia Viral Oncogene Homolog 2 (HER2) rat ortholog (neu) and lacks CB2 and by a variety of biochemical and cell biology approaches in human breast cancer cells in culture and in vivo, upon modulation of CB2 expression by si/shRNAs and overexpression plasmids. CB2-HER2 molecular interaction was studied by colocalization, coimmunoprecipitation, and proximity ligation assays. Statistical tests were two-sided. [Results]: We show an association between elevated CB2 expression in HER2+ breast tumors and poor patient prognosis (decreased overall survival, hazard ratio [HR] = 0.29, 95% confidence interval [CI] = 0.09 to 0.71, P = .009) and higher probability to suffer local recurrence (HR = 0.09, 95% CI = 0.049 to 0.54, P = .003) and to develop distant metastases (HR = 0.33, 95% CI = 0.13 to 0.75, P = .009). We also demonstrate that genetic inactivation of CB2 impairs tumor generation and progression in MMTV-neu mice. Moreover, we show that HER2 upregulates CB2 expression by activating the transcription factor ELK1 via the ERK cascade and that an increased CB2 expression activates the HER2 pro-oncogenic signaling at the level of the tyrosine kinase c-SRC. Finally, we show HER2 and CB2 form heteromers in cancer cells. [Conclusions]: Our findings reveal an unprecedented role of CB2 as a pivotal regulator of HER2 pro-oncogenic signaling in breast cancer, and they suggest that CB2 may be a biomarker with prognostic value in these tumors., This work was supported by grants from Spanish Ministry of Economy and Competitiveness (PI11/00295 and PI14/01101, supported with European Regional Development (FEDER) funds, to CS, SAF2012-36566 to JFP, SAF2010-22198 to SOG, and Ramón y Cajal fellowship to PJM); GW Pharmaceuticals (to CS); Madrid Regional Government (S2010/BMD-2308 to MG, S2010/BMD-2353 to SOG and S2011/BMD-2470 to JFP); Fundación Mutua Madrileña; Sandra Ibarra Foundation; and Instituto de Salud Carlos III (CIBERER-3–749/172.03 and ACCI-CIBERER-16 to JFP). EPG and EMV are recipients of Postdoctoral Research Contracts from Fundación Científica Asociación Española Contra el Cáncer. MA is a recipient of a Formación de Profesorado Universitario (FPU) fellowship (from the Spanish Ministry of Economy and Competitiveness), and EPG was a recipient of a Federation of the Societies of Biochemistry and Molecular Biology (FEBS) Short-term Fellowship.

Stromal fibroblasts influence tumor growth and progression. We evaluated two aldo–keto reductases, AKR1C1 and AKR1C2, in stromal fibroblasts and carcinoma cells as prognostic factors in primary human breast cancer. They are involved in intratumoral progesterone metabolism. Immunohistochemistry was performed on tissue microarrays from 504 core biopsies from breast cancer patients. Primary endpoints were disease-free (DFS) and overall (OS) survival. AKR1C1 and AKR1C2 expression in fibroblasts and tumor cells correlated with favorable tumor characteristics, such as small tumor size and negative nodal status. In univariate analysis, AKR1C1 expression in carcinoma cells correlated positively with DFS und OS; AKR1C2 expression in both fibroblasts and tumor cells also showed a positive correlation with DFS and OS. In multivariate analysis, AKR1C1 expression in carcinoma cells was an independent prognostic marker. It can be assumed that our observations are due to the independent regulatory function of AKR1C1/2 in progesterone metabolism and therefore provide a basis for new hormone-based therapy options for breast cancer patients, independent of classic hormone receptor status.