Tumor Immunology

We study of interactions of growth factors, cytokines and hormones in breast cancer, a field in which we have made original contributions at the international level.

The laboratory has exhaustively characterized the mechanisms involved in proliferation induced by progestins in breast cancer. We have shown that breast cancer cell proliferation is driven by the bidirectional interaction between progestins and growth factors. We are currently studying the nuclear function of ErbB-2 and the therapeutic relevance of its inhibition in breast cancer. We demonstrated that both heregulin (an ErbBs ligand) and progestins induce nuclear ErbB-2 migration, which stimulates cell proliferation. By using an ErbB-2 mutant that is unable to translocate to the nucleus (called hErbB-2∆NLS mutant), we were able to inhibit the growth of breast carcinomas. We also revealed that the nuclear function of ErbB-2 is involved in resistance to the action of trastuzumab. Indeed, we demonstrated that blockade of nuclear ErbB-2 localization suppresses tumor growth in a preclinical model of resistance to trastuzumab and would constitute a novel therapeutic strategy for the treatment of these tumors. We also found that the role of nuclear ErbB-2 as a transcription factor coactivator and its direct role as transcription factor upregulate microRNA-21 (miR-21) and promote BC metastasis. Our findings challenge the paradigm of anti-ErbB-2 drug design and highlight nuclear ErbB-2 as a novel target to overcome Ttzm resistance. Likewise, we have shown that the nuclear function of ErbB-2 is essential for the growth of triple-negative breast cancer and that nuclear ErbB-2 expression is a biomarker of poor clinical outcome in these patients. We continue exploring the molecular mechanisms through which ErbB-2 exerts its nuclear functions.

Tumor Immunology Group
We have demonstrated that the expression of the glycoprotein mucin 4 (MUC4) in HER2 positive breast cancer cells induces resistance to trastuzumab. We have determined that tumor necrosis alpha (TNFα), a proinflammatory cytokine, is the responsible of increasing MUC4 expression in HER2 positive breast cancer tumors. TNFα blockade, using antibodies against TNFα that are used in the clinic to treat inflammatory diseases such as rheumatoid arthritis among others, sensitizes HER2 positive tumors to trastuzumab and mounts an effective antitumoral immune response. We have also shown that MUC4 expression in HER2 positive breast cancer samples is an independent biomarker of poor trastuzumab response. Given these results, we are currently working on establishing the determination of MUC4 expression as a biomarker for HER2 and MUC4 positive breast cancer patients to assign the anti-HER2 therapies in combination with TNFα blocking agents to avoid or overcome resistance to treatment.