MAP17 is a small, 17-kDa, non-glycosylated membrane protein that is overexpressed in a percentage of carcinomas. In the present work, we have analyzed the role of MAP17 expression during mammary cancer progression. We have found that MAP17 is expressed in 60% human mammary tumors while it is not expressed in normal or benign neoplasias. MAP17 levels increased with breast tumor stage and were strongly correlated with mammary tumoral progression. A significant increase in the levels of reactive oxygen species (ROS) was observed in MAP17-expressing cells, as compared with parental cells. This increase was further paralleled by an increase in the tumorigenic capacity of carcinoma cells but not in immortal non-tumoral breast epithelial cells, which provides a selective advantage once tumorigenesis has begun. Expression of specific MAP17 shRNA in proteinexpressing tumor cells reduced their tumorigenic capabilities, which suggests that this effect is dependent upon MAP17 protein expression. Our data show that ROS functions as a second messenger that enhances tumoral properties, which are inhibited in non-tumoral cells. We have found that p38a activation mediates this response. MAP17 triggers a ROS-dependent, senescence-like response that is abolished in the absence of p38a activation. Furthermore, in human breast tumors, MAP17 activation is correlated with a lack of phosphorylation of p38a. Therefore, MAP17 is overexpressed in late-stage breast tumors, in which oncogenic activity relies on p38 insensitivity to induce intracellular ROS.

Somatic cells show a spontaneous decline in growth rate in continuous culture. This is not related to elapsed time but to an increasing number of population doublings, eventually terminating in a quiescent but viable state termed replicative senescence. These cells are commonly multinucleated and do not respond to mitogens or apoptotic stimuli. Cells displaying characteristics of senescent cells can also be observed in response to other stimuli, such as oncogenic stress, DNA damage, or cytotoxic drugs and have been reported to be found in vivo. Most tumors show unlimited replicative potential, leading to the hypothesis that cellular senescence is a natural antitumor program. Recent findings suggest that cellular senescence is a natural mechanism to prevent undesired oncogenic stress in somatic cells that has been lost in malignant tumors. Given that the ultimate goal of cancer research is to find the definitive cure for as many tumor types as possible, exploration of cellular senescence to drive towards antitumor therapies may decisively influence the outcome of new drugs. In the present paper, we will review the potential of cellular senescence to be used as target for anticancer therapy.

Abstract:The concept of senescence as a barrier to tumorigenesis, either by natural replicative limits or as stress-induced senescence deserves a critical evaluation of the benefits that can be achieved for cancer diagnosis and therapy. It is accepted that neoplastic cells can be forced to undergo senescence by genetic manipulations and by epigenetic factors, including anticancer drugs, radiation and differentiating agents. Senescent features can be imposed even in the absence of the two functional effector pathways, p53 and pRb, paving the way for speculation about the possible benefits of inducing an unspecific senescence program to stop tumor growth. In the present work we will review the potential of cellular senescence to be used as target for anticancer therapy.

Bypassing cellular senescence is a prerequisite step in the tumorigenic transformation. It has long been known that loss of a key tumour suppressor gene, such as p53 or pRB, is necessary but not sufficient for spontaneous cellular immortalisation. Therefore, there must be additional mutations and/or epigenetic alterations required for immortalisation to occur. Early work on these processes included somatic-cell genetic studies to estimate the number of senescence genes and nowadays are completed by in vivo models and with the requirements to bypass senescence induced by oncogenic transformation in stem cells. These principal studies laid the foundation for the field of senescence/immortalisation but were labour intensive and the results were somewhat limited. Using retroviral-based functional genetic screening, we and others identified universal genes regulating senescence/immortalisation (either by gain or loss of function) and found that some of these genes are widely altered in human tumours. We also explored the molecular mechanisms throughout these genes that regulate senescence and established the causality of the genetic alteration in tumorigenesis. The identification of genes and pathways regulating senescence/immortalisation could provide novel molecular targets for the treatment and/or prevention of cancer.