Prognostic significance of cyclins A2, B1, D1, and E1 and CCND1 numerical aberrations in oral squamous cell carcinomas

We analysed the expression of cyclins A2, B1, D1, and E1 by immunohistochemistry and numerical aberrations in CCND1 gene by fluorescence in situ hybridization technique in 67 primary oral squamous cell carcinomas (OSCC). Cyclin A2 expression was observed in 54 (83.1%) tumours, cyclin D1 in 58 (89.2%), cyclin B1 in 39 (60%), and cyclin E in 21 (32.8%). CCND1 region analysis revealed 26 (43.3%) tumours with the presence of numerical aberrations which were correlated with cyclin D1 high expression (Rho = 0.48; p < 0 001). Twenty-nine (45.3%) tumours were classified as high proliferative tumours assessed by Ki-67 protein expression and correlated with tumours with high expression of cyclin A2 (Rho = 0.30; p = 0 016) and cyclin B1 (Rho = 0.37; p = 0 003). In multivariate analysis for an overall five-year survival (OS), we found an adverse independent prognostic value for cyclin A2 high expression (p = 0 031) and for advanced tumour stage (p < 0 001). Our results confirm that several cyclins are commonly expressed in OSCC. CCND1 gene is abnormal in more than one-third of the cases and is frequently associated with cyclin D1 high expression. Moreover, cyclin A2 high expression is an independent indicator of worse OS suggesting that this protein may serve as a reliable biological marker to identify high-risk subgroups with poor prognosis.This study was supported by a grant from the Fundación de Investigación Médica Mutua Madrileña (Spain) and Instituto de Salud Carlos III (FIS PI 061902). The authors also thank the Biobanco del Complejo Hospitalario Universitario de Santiago and IINFACTS in CESPU (BubOral CESPU 2017; MacrOral CESPU 2017)S

Selective targeting of collagen IV in the cancer cell microenvironment reduces tumor burden

Goodpasture antigen-binding protein (GPBP) is an exportable1 Ser/Thr kinase that induces collagen IV expansion and has been associated with chemoresistance following epithelial-to-mesenchymal transition (EMT). Here we demonstrate that cancer EMT phenotypes secrete GPBP (mesenchymal GPBP) which displays a predominant multimeric oligomerization and directs the formation of previously unrecognized mesh collagen IV networks (mesenchymal collagen IV). Yeast twohybrid (YTH) system was used to identify a 260SHCIE264 motif critical for multimeric GPBP assembly which then facilitated design of a series of potential peptidomimetics. The compound 3-[4''-methoxy-3,2'-dimethyl-(1,1';4',1'')terphenyl-2''-yl]propionic acid, or T12, specifically targets mesenchymal GPBP and disturbs its multimerization without affecting kinase catalytic site. Importantly, T12 reduces growth and metastases of tumors populated by EMT phenotypes. Moreover, low-dose doxorubicin sensitizes epithelial cancer precursor cells to T12, thereby further reducing tumor load. Given that T12 targets the pathogenic mesenchymal GPBP, it does not bind significantly to normal tissues and therapeutic dosing was not associated with toxicity. T12 is a first-in-class drug candidate to treat cancer by selectively targeting the collagen IV of the tumor cell microenvironment.This work was supported by grants: PET 2006_0721, TRA2009_0026, IPT-010000-2010-45, IPT-2011-1527- 010000, RTC-2014-2415-1, PCB-010000-2010-031, PCB- 010000-2010-032, EQU-2014-1-0301 of the Plan Nacional de Investigación, Desarrollo e Innovación of the Spanish Government and IMGESA/06/78, IMGESA/06/79 of Conselleria d’Empresa, Universitat i Ciencia of Generalitat Valenciana to Fibrostatin, S.L. and J.S.; SAF 2001/0453, SAF 2003-09772-C03-01, SAF 2006-12520-C02-01, SAF 2009-10703 of the Plan Nacional de Investigación, Desarrollo e Innovación of the Spanish Government and PROMETEO/2009/065, PROMETEOII/2014/048 of Conselleria de Educaciò of Generalitat Valenciana to J.S. Additional funding came from ERESA, BioStratum Inc. and NephroGenex Inc. R&D programs, and personal funding from Vicente Saus and Carmen Cano to J.S.. Torres Quevedo program of the Spanish Government granted F.R., F-R-R., R.B., E.L-P and A.P-S.Medicin

Family History and Breast Cancer Hormone Receptor Status in a Spanish Cohort

Breast cancer is a heterogenous disease that impacts racial/ethnic groups differently. Differences in genetic composition, lifestyles, reproductive factors, or environmental exposures may contribute to the differential presentation of breast cancer among Hispanic women.A population-based study was conducted in the city of Santiago de Compostela, Spain. A total of 645 women diagnosed with operable invasive breast cancer between 1992 and 2005 participated in the study. Data on demographics, breast cancer risk factors, and clinico-pathological characteristics of the tumors were collected. Hormone receptor negative tumors were compared with hormone receptor postive tumors on their clinico-pathological characteristics as well as risk factor profiles.Among the 645 breast cancer patients, 78% were estrogen receptor-positive (ER+) or progesterone receptor-positive (PR+), and 22% were ER−&PR−. Women with a family history of breast cancer were more likely to have ER−&PR− tumors than women without a family history (Odds ratio, 1.43; 95% confidence interval, 0.91–2.26). This association was limited to cancers diagnosed before age 50 (Odds ratio, 2.79; 95% confidence interval, 1.34–5.81).An increased proportion of ER−&PR− breast cancer was observed among younger Spanish women with a family history of the disease