No abstract

The primary end point of the study was met, with a relative increase of 80% in the pCR rate achieved with chemotherapy plus trastuzumab and lapatinib compared with chemotherapy plus either trastuzumab or lapatinib. These data add further evidence supporting the superiority of a dual-HER2 inhibition for the treatment of HER2-positive breast cancer.

The ubiquitin-proteasome system plays a key regulatory role in cellular homeostasis. The inhibition of the 26S proteasome by Bortezomib leads to the accumulation of misfolded proteins, resulting in endoplasmic reticulum stress followed by a coordinated cellular response called unfolded protein response (UPR). Endoplasmic reticulum stress is also a potent inducer of macroautophagy. Bortezomib is a selective and potent inhibitor of the 26S proteasome and is approved for the treatment of multiple myeloma. Clinical trials with Bortezomib have shown promising results for some types of cancers, but not for some others, including those of the breast. In this study, we show that Bortezomib induces the UPR and autophagy in MCF7 breast cancer cells. Surprisingly, Bortezomib did not induce phosphorylation of PERK, a key initial step of the UPR. We show that induction of autophagy by Bortezomib is dependent on the proteasomal stabilisation of ATF4 and up-regulation of LC3B by ATF4. We show that ATF4 and LC3B play a critical role in activating autophagy and protecting cells from Bortezomib-induced cell death. Our experiments also reveal that HDAC6 knockdown results in decreased LC3B protein and reduced autophagy. Our work shows that the induction of autophagy through ATF4 may be an important resistance mechanism to Bortezomib treatment in breast cancer, and targeting autophagy may represent a novel approach to sensitize breast cancers to Bortezomib.

Purpose: To investigate the relationship of hypoxia-inducible factor-1a (HIF-1a) tumor expression in predicting the response to epirubicin and disease-free survival (DFS) in patients with breast cancer enrolled in a single institution trial of primary anthracycline and tamoxifen therapy. Experimental Design: The expression of HIF-1a was assessed by immunohistochemistry in 187 patients with T 2-4 N 0-1 breast cancer enrolled in a randomized trial comparing four cycles of single agent epirubicin versus epirubicin + tamoxifen as primary systemic treatment. All patients postoperatively received four cycles of the four weekly i.v. CMF regimen (cyclophosphamide, methotrexate, and 5-fluorouracil). Patients with estrogen receptor (ER)-positive primary tumors also underwent 5 years of treatment with adjuvant tamoxifen. Carbonic anhydrase IX (CAIX) was also scored as a marker of HIF activity. Results: Overall response to therapy progressively decreased with increasing tumor HIF-1a (P < 0.05), and HIF-1awas an independent predictor of response (P < 0.048). HIF-1aexpression was also associated with a significantly shorter DFS (P < 0.02) in all patients and in ER-positive but not in ER-negative patients. Furthermore, CAIX positivity conferred a significantly shorter DFS (P = 0.02) compared with CAIX-negative tumors in patients with HIF-1a-negative tumors. Conclusions: HIF-1a expression in patients with breast cancer is a marker of poor therapy response and outcome, especially in ER-positive patients. The combination of two hypoxia markers has greater utility than assessing just one, and patients with hypoxia markers in their tumors may be suitable for administration of drugs that reduce HIF-1a expression and increase oxygen delivery to the tumor bed before starting neoadjuvant therapies.Tumor growth and metastasis is dependent on the generation of a neovasculature. However, newly formed vessels function poorly in supplying oxygen and nutrient requirements in many tumors. Hypoxia, the pathophysiologic consequence of the structurally and functionally disturbed microcirculation (1), is therefore a common feature in solid tumors. Tumors respond to cellular oxygen deprivation using the ubiquitous family of transcription factors known as hypoxia-inducible factors (HIF; ref. 2). Under normal oxygen tension, HIF-1a is hydroxylated by specific prolyl hydroxylases, leading to recognition and binding by the von Hippel-Lindau protein, and targeting for degradation through the proteasome. In conditions of hypoxia, molecular oxygen is not available for hydroxylase activity, which leads to HIF-1a protein stabilization and translocation to the nucleus where it binds to aryl hydrocarbon nuclear translocators resulting in the activation of several gene pathways involved in angiogenesis, glycolysis, erythropoiesis, and apoptosis (see ref.3). Overexpression of HIF-1a protein has been identified in many tumor types (4), with high levels influencing the growth rate and metastatic potential of these cancers. In breast cancers, the frequen...

This meta-regression analysis of 29 heterogeneous neoadjuvant trials does not support the use of pCR as a surrogate end point for DFS and OS in patients with breast cancer. However, pCR may potentially meet the criteria of surrogacy with specific systemic therapies.