Tumor stroma is typically stiffer than selleck Ceritinib normal stroma. In breast cancer, diseased tis sue can Inhibitors,Modulators,Libraries be 10 times stiffer than normal breast. It is known that abnormal ECM stiffness plays an important role in cancer progression, but the mechanisms by which stiffness influences cancer progression are still under Inhibitors,Modulators,Libraries investigation. If we assume that we have discovered a general reaction of mammary epithelial cells to mechan ical strain, we envisage that epithelial cells in a stiff, mechanically dynamic tumor environment may react by inducing a SAP dependent Mkl1 gene set that in turn affects tumor progression. Furthermore, the products of these genes, many of which are involved in ECM turn Inhibitors,Modulators,Libraries over and function, for example Lox, Mmps, Adamts16 or Wisp1 might themselves manipu late the tumor microenvironment, thereby influencing tumor cell survival by a positive tumorigenic feedback loop.

Finding how to switch the mode of action of Mkl1 be tween SRF transactivation versus its SAP dependent Inhibitors,Modulators,Libraries transcriptional activity is a subject of ongoing research in our lab that in future may help with the development of new therapeutic interventions for breast cancer. Post translational modifications such as sumoylation are known to influence Mkl1 transcriptional activity and phos phorylation has been shown to influence interaction of Mkl1 with nuclear actin resulting in transcriptional changes. Further characterization of these and other post transcriptional changes of Mkl1 deserve spe cial attention when trying to answer the above question.

Conclusions In the current study, we discovered a breast cancer specific set of genes that is highly interesting as a prog nostic marker and therapeutic target for several reasons. The expression of this gene set is regulated by Mkl1 and its SAP domain Inhibitors,Modulators,Libraries and is independent of SRF. The SAP dependent, SRF independent Mkl1signaling is trig gered by mechanical strain and may thus be activated in stiff tumors with a high stromal content and high inter stitial tissue pressure. This gene set is composed of interesting members some of which represent novel candidates for playing a functional role in cancer and others that have already been implicated in cancer related functions, as for example tenascin C, a meta static niche component important for lung colonization, or Lox as a gene mediating collagen crosslinking re sponsible for fibrosis enhanced metastasis.

The SAP dependent Mkl1 target genes are associated with a poor clinical outcome in breast cancer patients, not re ceiving adjuvant therapy or having a cancer classified as non aggressive Enzalutamide chemical structure such as LN negative, ER positive, Grade 1 or 2 tumors. This makes these genes potential valuable prognostic markers in selecting patients who may benefit from an immediate and or more aggressive therapy.