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Page 534 Belizario et al. Cancer Drug Resist 2019;2:527-38 I http://dx.doi.org/10.20517/cdr.2018.009
[53]
cancer data . The differential activity of TFs associated to mutant PIK3CA in isogenic breast cancer cell
lines was revealed by comparing the phospho (p)-AKT and p-S6K levels [53,54] . The results point toward the
possible application of these predictive models to screening of drugs to personalized therapies.

Epigenetic studies have found that luminal breast cancers share a common epigenetic signature, whereas
basal-like breast cancers display highly heterogeneous signatures [55,56] . Basal-like breast cancer cells that
constitute the majority of TNBCs can reprogram a subset of luminal breast cancer cells to a basal-like state,
which drastically alter their phenotype. This phenotype is associated with high production of the cytokine
[56]
IL-6 and tumor-promoting molecules . Overexpression of three TFs Engrailed 1, T box transcription 18,
and T-cell factor 4 can induce the repression of some luminal features in luminal breast cancer cells .
[56]
Over 75% of breast tumors express the ERα that leads to genetic and cellular aberrations [38,39] . Patients with
ERα-dependent tumor growth often respond well to tamoxifen and fulvestrant [38,39] . Nonetheless, patients
may develop endometrial cancer and increased bone density. Recent studies using ChIP-seq and chromatin
accessibility (DNase-seq and ATAC-seq) assays have identified a unique cistrome ERα profile for breast
[57]
cancers . The TF FOXA1 was found as an essential TF for estrogen binding and induction of ERα-
mediated gene expression in breast cancer cells [58,59] . Therefore, targeting FOXA1 with small molecules may
disrupt ERα positive breast tumor growth. The cyclin D and cyclin-dependent kinases 4 and 6 (CDK4/6)
have critical roles in breast carcinogenesis [29,30] . Experimental chemotherapy with small molecule inhibitors
of CDK/6, such as abemaciclib, palbociclib and ribociclib, have yielded clinical benefits to ER positive
breast cancer patients . Abenamaciclib decreases cell proliferation and enhances tumor cell intracellular
[60]
levels of endogenous retroviral genes, triggering “viral mimicry”. This in turn stimulates production of
type III IFNs and IFN-induced genes in an autocrine fashion [60,61] . Accordingly, treatment of cancer cells
with abemaciclib markedly decrease DNMT1 mRNA levels and DNA methylation, therefore, functioning
[62]
in the similar way as epigenetic modifier 5-azacytidine . Finally, epigenetic changes at enhancers and
promoters of breast cancer cells as well as tumor stroma cells such as CAFs and myoepithelial cells are
critical for transformation and metastasis [20,24] . CAFs may also contribute to immune suppressive effect
[63]
of TME that is one specific biological feature of HER2/neu-positive breast cancers . Therefore, DNA
demethylating agents and cell cycle checkpoint inhibitors may be promise therapies to breast cancers.

Immunophenopying has been proposed as an biological assay to classify tumors and their
microenvironments [21-23] . A classification into inflamed and non-inflamed tumors, and presence
of the immune cells, especially T cells, have been used as an indicator of clinical response to the
immunotherapies [19-21] . The immune-inflamed phenotype is rich in immune cells responsive to the immune
checkpoint monoclonal antibodies towards CTLA-4 and PD-1, as well as its ligands PD-L1 and PD-
L2. These mAbs are highly effective and specific, however, the main drawback of immunotherapies is
heterogeneity of response rate, estimated from 10%-40% . CD8+ T-cell infiltration increases significantly
[64]
[64]
with tumor mutation load . The presence of both PD-L1 expression on breast tumor cells and TILs
in TME predict longer disease-free survival and better overall survival to TNBC patients . One study
[65]
[66]
investigated the role of PD-1 as a prognostic marker for TNBC in an Asian cohort of 269 patients . The
results suggested a superior prognostic value of the CD274 (PDCD1 ligand 1, PD-L1) and PDCD1 in TNBC
[66]
tumor immune microenvironment as compared to classical clinicopathological parameters . Overall
the results of these studies are providing new insights and alternative routes for possible therapeutic
interventions to breast cancers.

An increased number of commensal and pathogenic bacteria, including Fusobacterium nucleatum,
Bacteroides fragilis, Enterococcus faecalis, Streptococcus gallolyticus, Helicobacter hepaticus, and Porphyromonas
gingivalis have been associated with cancer development. On the other hand, Faecalibacterium prausnitzii,
Akkermansia muciniphila, Bifidobacterium longum, Collinsella aerofaciens and Citrobacter rodentium seem