Genes that mediate breast cancer metastasis to lung

Abstract

By means of in vivo selection, transcriptomic analysis, functional verification and clinical validation, here we identify a set of genes that marks and mediates breast cancer metastasis to the lungs. Some of these genes serve dual functions, providing growth advantages both in the primary tumour and in the lung microenvironment. Others contribute to aggressive growth selectively in the lung. Many encode extracellular proteins and are of previously unknown relevance to cancer metastasis.Metastasis is frequently a final and fatal step in the progression of solid malignancies. Tumour cell intravasation, survival in circulation, extravasation into a distant organ, angiogenesis and uninhibited growth constitute the metastatic process 1 . The molecular requirements for some of these steps may be tissue specific. Indeed, the proclivity that tumours have for specific organs, such as breast carcinomas for bone and lung, was noted more than a century ago 2 .The identity and time of onset of the changes that endow tumour cells with these metastatic functions are largely unknown and are a subject of debate. It is believed that genomic instability generates large-scale cellular heterogeneity within tumour populations, from which rare cellular variants with augmented metastatic abilities evolve through a darwinian selection process 2,3 . Work on experimental metastasis with tumour cell lines has demonstrated that reinjection of metastatic cell populations can lead to enrichment in the metastatic phenotype 4-6 . Recently, however, the existence of genes expressed by rare cellular variants that specifically mediate metastasis has been challenged 7 . Transcriptomic profiling of primary human carcinomas has identified gene expression patterns that, when present in the bulk primary tumour population, predict a poor prognosis for patients 8-10 . The existence of such signatures has been interpreted to mean that genetic lesions acquired early in tumor-igenesis are sufficient for the metastatic process, and that consequently no metastasis-specific genes exist. However, it is unclear whether these genes predicting metastatic recurrence are also functional mediators.The lungs and bones are frequent sites of breast cancer metastasis, and metastases to these sites differ in terms of their evolution, treatment, morbidity and mortality 11 . Reasoning that each organ places different demands on circulating cancer cells for the establishment of metastases, Selection of cells metastatic to the lungsThe cell line MDA-MB-231 was derived from the pleural effusion of a breast cancer patient suffering from widespread metastasis years after removal of her primary tumour 12 . Individual MDA-MB-231 cells grown and tested as single-cell-derived progenies (SCPs) have distinct metastatic abilities and tissue tropisms 13 despite having similar expression levels of genes constituting a validated Rosetta-type poor prognosis signature 9 ( Supplementary Fig. S1). These different meta-static behaviours, including different tropisms to bone and lung, ...

Transcriptomal profiling of the cellular response to DNA damage mediated by Slug (Snai2)

“…However, majority of Snai2-target genes (Atm, Bid, p27, Mt1, Cxcl1, Foxg1 and Fos) were downregulated in Snai2-deficient MEFs in response to DNA damage, supporting the view that Snai2 can also behave as a positive transcriptional regulator or act by repressing the transcription of a repressor (Bermejo-Rodriguez et al, 2006). All these novel Snai2 targets have been implicated in DNA damage and survival regulation (Wang et al, 1991;Beattie et al, 1998;Park et al, 2000;Nanda et al, 2001;Katoh and Katoh, 2004;Minn et al, 2005). Thus, the regulation of these genes by Snai2 in response to DNA damage could be important in preserving integrity of tumour target cells and supports the view that failure to control Snai2 expression can produce cancer and alterations in development (Perez-Mancera et al, 2005;Perez-Mancera et al, 2006).…”

Targeted inhibition of fascin function blocks tumour invasion and metastatic colonization

“…In addition to breast cancers, elevated levels of fascin have been found in other metastatic tumours and are correlated with clinically aggressive phenotypes, poor prognosis and shorter survival 32 fascin is specifically overexpressed in many types of metastatic tumour cells [37][38][39][40] . Fascin is also one of the gene signatures that correlate with breast cancer metastasis to the lung 57 .…”

Data driven derivation of cutoffs from a pool of 3,030 Affymetrix arrays to stratify distinct clinical types of breast cancer

“…We included 238 of our own samples (datasets Frankfurt, Frankfurt-2, and Frankfurt-3) which have been described previously (Ahr et al 2002 [9], [10], Rody et al 2008 [11], Ruckhäberle et al 2008 [12], and Rody et al 2007 [13], respectively) as well as 2792 samples from 22 different publicly available datasets (Table 1): Rotterdam [14][15][16], Mainz [17], Trans-BIG [18], Oxford-Untreated [19], London [20], London-2 [21], Oxford-Tamoxifen, Veridex-Tam [22], Stockholm [23], Uppsala [24,25], San Francisco [26], New York [27], MDA133 [28], EORTC [29], Edinburgh [30], ExpO [31], Signapore [32], Genentech [33], Boston [34], Berlin [35], Paris [36], and Tampa [37]. For comparability, only the ProbeSets from the Affymetrix HG-U133A microarray were used from seven datasets where HG-U133?…”