Nuclear Receptors and Breast Cancer

Dra. Vivanco Lab


This group belongs to CIC bioGUNE, a research center located just outside Bilbao. This center carries out research in various fields, including the study of cancer. The group focuses on the study of the mechanisms by which nuclear receptors, particularly the estrogen receptor (ER), influence breast stem cell behavior (both in healthy stem cells and cancer stem cells). The group’s recent results have revealed the involvement of cancer stem cells in the development process of hormone therapy resistance. The results also highlight the molecular heterogeneity observed in response to the cellular microenvironment.

About Us

Principal Investigators:
María del Mar Vivanco Ruiz

Doctoral Fellows:
Miriam Rábano
So Young Lee

Predoctoral Fellows:
Iskander Aurrekoetxea
Julia San Millán

What Do We Research?

Breast cancer is the most common tumor among women. It is a highly heterogeneous disease that raises a lot of questions that remain unanswered, such as, for example:

– How do some cells become resistant to treatments?

– When treatment fails and the tumor reappears, why is it more aggressive?

– How do cells escape from the tumor and initiate metastasis in other parts of the body?

Mammary tumors are not made up of a homogeneous mass; rather, they contain different cell types, including cells with stem cell characteristics. These cells are called cancer stem cells (CSCs), and they are responsible for tumor initiation and for the reappearance of tumors after treatment. In our lab we study:

– The enormous heterogeneity of breast cancer

– The resistance of certain tumors to current therapies

– The molecular mechanisms involved in this resistance

These studies are carried out with the hope that their findings facilitate the search for new forms of therapy that, combined with current therapies, result in more efficient treatments that increase the survival rate of breast cancer patients.

A considerable proportion of localized breast cancer patients and all patients with metastasis develop resistance to therapy. This resistance is a true clinical and biological challenge. It is necessary to improve our understanding of the cancer stem cells responsible for the development of resistance to therapy in order to find ways to prevent and control the reappearance of the tumor after treatment.

In our lab, we study how cancer stem cells support the tumor and provide it with signal supplies so it can grow, become more resistant to treatment, and facilitate relapse (a reappearance of the tumor) and metastasis. At a molecular level, we have observed that cancer stem cells do not have an estrogen receptor, the receptor on which tamoxifen acts. Thus, this treatment does not affect stem cells and cannot kill them. Moreover, we have discovered that tamoxifen resistant tumors are more aggressive and contain a higher proportion of stem cells and high levels of a protein called Sox2, which is important for stem cell maintenance. Finally, we have observed that the development of tamoxifen resistance depends on Wnt signaling pathway activation in cancer stem cells, precisely of Sox2. These findings allowed us to suggest that a combination of hormone therapy with Sox2 and/or Wnt inhibitors could constitute a new strategy for the treatment of specific kinds of breast cancer and for the prevention of their recurrence.

Likewise, these studies indicate the potential of Sox2 as a biomarker for hormone therapy resistance. We are exploring this possibility in a prospective study in collaboration with three hospitals. In order to keep decoding the complexity of the therapy resistance problem, we have designed tamoxifen resistance cell models that will allow us to study the genetic profile of tumor cells with high and low Sox2 levels (and levels of other proteins involved), as well as the effect of tumor microenvironment. This study will produce new molecular data on how a lack or an excess of Sox2 affects cancer stem cell propagation and relapse.

In conclusion, this study can identify new paths that facilitate the development of treatments that eradicate cancer stem cells, reduce the risk of tumor reappearance, and prevent the development of metastasis. Moreover, these studies contribute to the accumulation of information for the development of precision medicine or personalized medicine, which will design specific treatments according to the characteristics of each patient’s tumor.


  1. Acquired resistance of ER- positive breast cancer to endocrine treatment confers an adaptive sensitivity to TRAIL through post-translational downregulation of c-FLIP.
    Piggott L, da Silva AM, Robinson T, Santiago-Gómez A, Simões BM, Becker M, Fichtner I, Andera L, Piva M, Vivanco MD, Morris C, Alchami FS, Young P, Barrett-Lee PJ, Clarke RB, Gee JM, Clarkson R.
    Clin Cancer Res. 2018 May 15;24(10):2452-2463. PMID: 29363524
  2. MiR-24 induces chemotherapy resistance and hypoxic advantage in breast cancer.
    Roscigno G, Puoti I, Giordano I, Donnarumma E, Russo V, Affinito A, Adamo A, Quintavalle C, Todaro M, Vivanco MdM, Condorelli G.
    Oncotarget 2017 8(12):19507-19521. PMID: 28061479
  3. Stratification and therapeutic potential of PML in metastatic breast cancer.
    Martín-Martín N, Piva M, et al., Vivanco MdM, Matheu A, Gomis RR, Carracedo A.
    Nature Communications 2016 Agu 24;7:12595. PMID: 27553708
  4. Distinct breast cancer stem/progenitor cell populations require either HIF1a or loss of PHD3 to expand under hypoxic conditions.
    Iriondo O, Rábano M, Domenici G, Carlevaris O, López-Ruiz JA, Zabalza I, Berra E, Vivanco MdM.
    Oncotarget 2015 Oct 13;6(31):31721. PMID: 26372732
  5. Paracrine Met signalling triggers epithelial-mesenchymal transition in mammary luminal progenitors, affecting their fate.
    Di-Cicco A, Petit V, Chiche A, Bresson L, Romagnoli M, Orian-Rousseau V, Vivanco Md, Medina D, Faraldo MM, Glukhova MA, Deugnier MA.
    Elife 2015 Jul 13;4. PMID: 26165517
  6. FACS sorting mammary stem cells.
    Iriondo O, Rábano M, Vivanco MdM.
    Methods Mol Biol. 2015;1293:63-72. PMID: 26040681
  7. Human mammospheres secrete hormone-regulated active extracellular vesicles.
    Gonzalez E, Piva M, Rodriguez-Suarez E, Gil D, Royo F, Elortza F, Falcon-Perez JM, Vivanco MdM.
    PLoS One. 2014 Jan 3;9(1):e83955. PMID: 24404144
  8. Sox2 promotes tamoxifen resistance in breast cancer cells.
    Piva M, Domenici G, Iriondo O, Rábano M, Simões BM, Comaills V, Barredo I, López-Ruiz JA, Zabalza I, Kypta R, Vivanco MdM.
    EMBO Mol Med. 2014 Jan;6(1):66-79. PMID: 24178749
  9. Global dynamics of two-compartment models for cell production systems with regulatory mechanisms.
    Getto P, Marciniak-Czochra A, Nakata Y, Vivanco MdM.
    Math Biosci. 2013 Oct;245(2):258-68. PMID: 23891585
  10. Effects of estrogen on the proportion of stem cells in the breast.
    Simões BM, Piva M, Iriondo O, Comaills V, López-Ruiz JA, Zabalza I, Mieza JA, Acinas O, Vivanco MdM.
    Breast Cancer Res Treat. 2011 Aug;129(1):23-35. PMID: 20859678
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