BACKGROUNDIt has been suggested that genetic polymorphisms in certain glutathione‐S‐transferase (GST) genes reduce the effectiveness of detoxifying cytotoxins generated by chemotherapeutic agents, potentially resulting in enhanced clinical responses to chemotherapy.METHODSThe authors evaluated common polymorphisms in the GSTM1, GSTT1, and GSTP1 genes for associations with overall survival in 1034 patients with invasive breast carcinoma who were recruited into the Shanghai Breast Cancer Study between 1996 and 1998, treated with chemotherapy, and followed for a median of 5.3 years.RESULTSAfter adjusting for age, tumor stage, and the use of radiotherapy and tamoxifen, women who were homozygous for the variant GSTP1 105Val allele had a 60% reduction in mortality risk compared with women who were homozygous for the Ile allele (hazard ratio, 0.4; 95% confidence interval, 0.2–0.8). No association was found with respect to any of the GSTM1 or GSTT1 genotypes.CONCLUSIONSThe results of the current study indicate a potential role for GSTP1 polymorphism in predicting the clinical outcomes of patients with breast carcinoma who are treated with chemotherapy. Cancer 2005. © 2004 American Cancer Society.

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Highlights d Mechanical ring (MR) is interfacing between the invading and the engulfing cells d MR is a multi-molecular complex enriched in the mechanical sensor vinculin d Vinculin coordinates the polarized AJ and CA to promote entosis d MR, in addition to AJ and CA, is the third core element essential for entosis

Though homotypic cell-in-cell (hoCIC) structures are implicated in the development and progression of multiple human tumors, the molecular mechanisms underlying their formation remain poorly understood. We found that the expression of Protocadherin-7 (PCDH7), an integral membrane protein, was negatively associated with the formation of hoCIC structures. Overexpression of PCDH7 efficiently inhibits, while its depletion significantly enhances, hoCIC formation, which was attributed to its regulation on intercellular adhesion and contractile actomyosin as well. Via directly interacting with and inactivating PP1α, a protein phosphatase that dephosphorylates pMLC2, PCDH7 increases the level of pMLC2 leading to enhanced actomyosin at the intercellular region and compromised hoCIC formation. Remarkably, PCDH7 enhanced anchorageindependent cell growth in a hoCIC-dependent manner. Together, we identified PCDH7 as the first trans-membrane protein that inhibits hoCIC formation to promote tumor growth.

Homotypic cell-in-cell (CIC) structures forming between cancer cells were proposed to promote tumor evolution via entosis, a nonapoptotic cell death process. However, the mechanisms underlying their formation remained poorly understood. We performed a microarray analysis to identify genes associated with homotypic CIC formation. Cancer cells differing in their ability to form homotypic CIC structures were selected for the study. Association analysis identified 73 probe sets for 62 candidate genes potentially involved in CIC formation. Among them, twenty-one genes were downregulated while 41 genes were upregulated. Pathway analysis identified a gene interaction network centered on IL-8, which was upregulated in high CIC cells. Remarkably, CIC formation was significantly inhibited by IL-8 knockdown and enhanced upon recombinant IL-8 treatment, which correlated with altered cell-cell adhesion and expression of adhesive molecules such as P-cadherin and γ-catenin. Together, our work identified IL-8 as a positive regulator of homotypic CIC formation via enhancing intercellular adhesion.