Chromosome band 17q21 in breast cancer: Significant association between beclin 1 loss and HER2/NEU amplification

Abstract

Treatment success of breast cancer patients with trastuzumab alone or in combination depends not only on HER2/NEU amplification but also on PTEN and PI3K status and efficient cell death programs. In this pilot study, we found a significant association between loss of beclin 1 and HER2/NEU amplification (both on 17q21) in breast cancers. This finding was confirmed in two public copy number microarray datasets. Furthermore, there is a trend associating beclin 1 loss with TP53 mutations, PI3KCA gene gain, and PTEN mutations. Finally, the observation that beclin 1 gene loss predicted a response to trastuzumab alone or in combination with other drugs is worthy of further confirmation in larger cohorts. Our results suggest that, beclin 1 loss may contribute to genome instability and to a defective autophagy that may lead to tumoral cell death in presence of competent apoptosis or senescence pathways.

Autophagy regulation in the development and treatment of breast cancer

“…Given the prevalence of resistance in ER + breast cancers, autophagy inhibition might serve as an advantageous combination strategy for these subsets of breast cancer patients. Similarly, in a small cohort of breast cancer patients with HER2/c-neu amplification, the concomitant loss of Beclin-1 is significantly associated with better clinical response to trastuzimab, indicative of the cell deathpromoting aspect of autophagy in response to the targeted treatment [76]. This evidence supports the hypothesis that defective autophagy functions as a modifier, potentially a fundamental driver, of genomic damage during tumor progression.…”

“…On the other hand, overexpression of Beclin-1 leads to a decrease in MCF-7 cellular proliferation, and breast cancer formation occurs in nude mice. Furthermore, Negri et al [76] reported that Becn1 heterozygosity suppressed Palb2-associated mammary tumorigenesis by p53-dependent mechanism in Palb2 f/f ;Wap-Cre;Becn1 +/− mice.…”

The autophagic paradox in cancer therapy

“…Importantly, some of these abnormalities have been shown to correlate with clinicopathological parameters and disease outcomes including overall survival in cancer patients. These findings not only underscore a pivotal role of autophagy in tumorigenesis, but also highlight the possibility of using autophagy-associated molecules as novel prognostic markers in clinical settings (Russell et al, 1990;Eccles et al, 1992;Futreal et al, 1992;Cliby et al, 1993;Saito et al, 1993;Gao et al, 1995;Ahn et al, 2007;Miracco et al, 2007Miracco et al, , 2010Ding et al, 2008;Fujii et al, 2008;Yoshioka et al, 2008;Kim et al, 2008a;Kang et al, 2009;Lazova and Pawelek, 2009;Nomura et al, 2009;Othman et al, 2009;Pirtoli et al, 2009;Li et al, 2009Zhang et al, 2009a;Koukourakis et al, 2010;Lazova et al, 2010;Miao et al, 2010;Negri et al, 2010;Sivridis et al, 2010;Wan et al, 2010;Karpathiou et al, 2010;Chang et al, 2011;Ma et al, 2011).…”

Autophagy and genomic integrity

“…[22][23][24] Accordingly, a significant association between loss of beclin 1 and amplification of the HER2/ NEU oncogene was described in breast carcinoma. 25 Quenching ROS with N-acetyl l-cysteine (NAC) delayed the promotion of aneuploidy and improved survival of beclin 1 þ / À cells, revealing that ROS contributes to genomic instability in these cells. 23,24 Interestingly, expression of p62 increased ROS and DNA damage in autophagy-defective cells under metabolic stress, thereby revealing that p62 accumulation may potentiate generation of ROS due to dysfunctional mitochondria.…”