Molecular Mechanisms of Carcinogenesis

Molecular Mechanisms of Carcinogenesis

  • Patricia Elizalde Currículum Vitae

3- Immunology

ErbB-2-positive breast cancer (bearing ErbB-2 overexpression/amplification) and triple negative breast cancer (TNBC, defined by lack of expression of both estrogen and progesterone receptors as well as ErbB-2) are the breast cancer subtypes that have the highest rate of distant metastasis. Knowledge gleaned in this area will definitely impact patients’ survival and improve their quality of life.

In our lab we have developed a vaccination protocol based on the serial injection of breast cancer cells -whose oncoprotein Stat3 was previously blocked- that was able to inhibit TNBC growth in mice. We also observed an antimetastatic effect that was mediated by cells of the immune system called Natural Killer (NK) cells. Moreover, we observed that blockage of Stat3 in tumor cells turns on a “senescence program” accompanied by the secretion of a specific profile of protein mediators (cytokines). We are now dissecting these mediators to formulate an adjuvant suitable for metastasis control.

It is known that the treatment of choice of ErbB-2-positive breast cancer patients is the administration of trastuzumab, a humanized monoclonal antibody against ErbB-2. However, de novo and acquired resistance, with local and distant recurrence, limits the clinical benefit of this treatment. In this respect, we have demonstrated that the cytokine tumor necrosis factor alpha (TNFa) is a source of trastuzumab resistance in vivo and in vitro. We observed that TNFa induces ErbB-2 transactivation and is able to overcome the inhibitory effect of trastuzumab on proliferation in ErbB-2-positive cell lines. On the other hand, knockdown of TNFa in human cell lines that are de novo resistant to trastuzumab, turns them sensitive to the inhibition of this antibody. Our findings provide the basis of rational, combinatorial targeted therapy of both trastuzumab and TNFa-blocking agents that could be able to overcome trastuzumab resistance in the clinical setting.