Novel analysis of non-genetic features of cancer samples identifies factors related to cancer progression and metastatization.

A main challenge in cancer research nowadays, de facto preventing efficient patient treatment, resides in tumor heterogeneity, both across patients and within tumor masses -which means that tumor masses are made up of cells with different features. This requires ad hoc analyses to discriminate the distinct cell subpopulations constituting a tumor mass. Discrete cell subpopulations within the tumor mass may acquire resistance to anti-cancer drug therapy, as a consequence of a process that, as well as for cancer progression into metastases, has been suggested to be modulated by non-genetic mechanisms –such as those involving epigenetic* modifications. For instance, in Breast Cancer (BC), epigenetic mechanisms modulate Estrogen Receptor* (ER) binding to enhancers (regions of the DNA normally having a regulatory role, modulating the activation of specific genes). Estrogen receptors are a common target of endocrine therapy in cancer treatment, as by interfering –blocking estrogen receptors- with the hormonal signal normally triggering cell growth, therapy can slow down breast cancer progression.

  

Enhancers analysis. A recent analysis, consisting in “following” the epigenetic features of enhancers both in primary and in treatment resistant (estrogen therapy resistant) metastatic tumor samples, identified markers labeling cell subpopulations, within the tumor mass, expanding during BC progression.

 

Results of the analysis:

FOXA1. Notably, the enhancers/markers identified in discrete cell subpopulations labeled tumor progression specifically in BC, as they were present in metastatic BC samples as well as in primary BC samples, but not in colorectal cancer samples. This analysis enabled to identify a TF –a protein binding the DNA and ultimately modulating expression of specific target genes- exclusively present in discrete cell subpopulations of BC samples, related to cancer progression: FOXA1. FOXA1 is known to be indispensable for survival, due to its role in pancreatic and renal function as well as in mammary gland development, and more recently described as having a role in modulating estrogens (and androgens) action in breast cancer (and prostate cancer).

  

IL2*. This analysis identified also, in the cell subpopulations expanding during cancer progression, deactivated enhancers related to IL2 signaling, which has been proposed as a marker of relapse (meaning that patients showing reduced levels of IL2 concentration often relapse).

  

YY1 and SLC9A3RI. Moreover, they showed the transcription factor YY1 as having a lead role in BC progression, marking a cell subpopulation highly present in ER-positive, primary and therapy resistant metastatic BC samples, which means that ER-positive BC tumors contain a larger fraction of cells expressing YY1 compared to normal tissues, suggesting a role of YY1 in therapy resistance. A DNA region bound by YY1 and responsible for driving drug resistance has been identified in a gene (SLC9A3RI) potentially involved in metastatic invasion, whose expression, higher in BC tissue compared to normal tissue, correlates with poor patients’ prognosis.

 

Therefore, this recent article describes a novel analysis to identify non-genetic features linked to breast cancer progression, labeling subpopulations of cells resistant to therapy, whose identification and targeting might be therapeutically exploited.

 

 

 

 

*Epigenetics is the ensemble of the endogenous chemical modification of DNA and DNA-associated proteins such as histones, which are responsible for the 3D structure of the DNA.

 

*Estrogen Receptor. Proteins expressed in breast cells enabling them to respond to estrogen hormones. Estrogen receptor are targeted by of endocrine therapy in breast cancer.

 

*IL2. Molecule regulating growth and differentiation of immune system cells, sometimes used in cancer therapy in combination with other drugs.

 

 

 

Reference. Enhancer mapping uncovers phenotypic heterogeneity and evolution in patients with luminal breast cancer. Patten, Corleone, Győrffy, Perone, Slaven, Barozzi, Erdős, Saiakhova, Goddard, Vingiani, Shousha, Pongor, Hadjiminas, Schiavon, Barry, Palmieri, Coombes, Scacheri, Pruneri, Magnani. Nat Med. 2018 Sep.