Synergistic antitumor activity of lapatinib and retinoids on a novel subtype of breast cancer with coamplification of ERBB2 and RARA.

All-trans retinoic acid (ATRA), the only clinically available cyto-differentiating agent, has potential for the therapy/chemoprevention of breast carcinoma. Given the heterogeneous nature of this tumor, a rational use of ATRA and derivatives (retinoids) in the clinic requires the identification of patients that would benefit from retinoid-based protocols. Here, we demonstrate that 23-32% of the human ERBB2(+) breast cancers show coamplification of retinoic acid receptor alpha (RARA), encoding the retinoic acid receptor, RARα. This represents a novel subtype of breast cancer characterized by remarkable sensitivity to ATRA and RARα agonists, regardless of positivity to the estrogen receptor, a known modulator of retinoid sensitivity. In estrogen-receptor-negative cellular models showing coamplification of ERBB2 and RARA, simultaneous targeting of the corresponding gene products with combinations of lapatinib and ATRA causes synergistic growth inhibition, cyto-differentiation and apoptosis. This provides proof-of-principle that coamplification of ERBB2 and RARA can be exploited for the stratified and targeted therapy of a novel subtype of breast cancer patients, with an approach characterized by tumor cell selectivity and low predicted toxicity. The available cellular models were exploited to define the molecular mechanisms underlying the antitumor activity of combinations between lapatinib and ATRA. Global gene expression and functional approaches provide evidence for three components of the antiproliferative/apoptotic responses triggered by lapatinib+ATRA. Induction of the retinoid-dependent RARRES3 protein by ATRA stabilizes the effect of lapatinib inhibiting ERBB2 phosphorylation. Upregulation and activation of the transcription factor FOXO3A integrates ATRA-dependent transcriptional and lapatinib-dependent posttranscriptional signals, controlling the levels of effector proteins like the antiapoptotic factor, BIRC5. Stimulation of the TGFß pathway by ATRA mediates other components of the apoptotic process set in motion by simultaneous targeting of ERBB2 and RARα.

Dietary patterns, cardiovascular risk factors and C-reactive protein in a healthy Italian population.

BACKGROUND AND AIMS: Dietary habits have been associated with cardiovascular disease (CVD) risk factors. This study aimed at evaluating the association of non-predefined dietary patterns with CVD risk profile and C-reactive protein (CRP). METHODS AND RESULTS: We analyzed 7646 healthy subjects from the Moli-sani project, an on-going cross-sectional cohort study of men and women aged >or=35, randomly recruited from a general Italian population. The Italian EPIC food frequency questionnaire was used. Food patterns were generated using principal factor analysis (PFA) and reduced rank regression (RRR). Three dietary patterns were identified by PFA. The "Olive Oil and Vegetables" pattern, characterized by high intake of olive oil, vegetables, legumes, soups, fruits and fish, was associated with relatively lower values of glucose, lipids, CRP, blood pressure and individual global CVD risk score. The "Pasta and Meat" pattern, characterized by high intake of pasta, tomato sauce, red meat, animal fats and alcohol, was positively associated with glucose, lipids, CRP and CVD risk score. The "Eggs and Sweets" pattern, characterized by positive loadings of eggs, processed meat, margarines, butter, sugar and sweets, was associated with high values of CRP. The first RRR pattern was similar to the "Pasta and Meat" pattern both in composition and association with CVD risk profile. CONCLUSIONS: In a large healthy Italian population, non-predefined dietary patterns including foods considered to be rather unhealthy, were associated with higher levels of cardiovascular risk factors, CRP and individual global CVD risk, whereas a "prudent-healthy" pattern was associated with lower levels.