**4.5. Histone deacetylase inhibitors**

These drugs modulate gene expression through epigenetic regulation and can induce cell cycle arrest, differentiation, and apoptosis. Panobinostat is a potent pan-histone deacetylase inhibitor with preclinical activity in the TNBC. Several histone deacetylase inhibitors are currently being tested as treatment for metastatic TNBC in combination with chemotherapy or with immune checkpoint inhibitors [35].

factor-1α (HIF-1α) was strongly correlated to clinicopathological features in many types of cancers. This molecule seems to play a significant role in the development of different tumors

Triple-Negative Breast Cancer: Expression of Hypoxia-Inducible Factor 1α in Triple-Negative…

http://dx.doi.org/10.5772/intechopen.75354

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HIF-1α is responsible mainly for cellular adaptation to hypoxic conditions; therefore, genes triggered by this factor are responsible mainly for the improvement in oxygen supply (by increasing angiogenesis, broadening the lumen of existing vessels, increased erythropoiesis or increased iron consumption), adaptation of cells to anaerobic metabolism conditions as well as for other changes facilitating cell survival in insufficient oxygen availability and modifying the main metabolic pattern. Stimulation of angiogenesis promotes the increased risk of distant metastases. Better accessibility of blood vessels increases the chance of tumor cells finding their way into the bloodstream and being transported to niches allowing settlement

Hypoxia-inducible factor 1 is a master transcriptional regulator of genes regulating oxygen homeostasis. The HIF-1 protein is composed of two HIF-1α and HIF-1β/aryl hydrocarbon receptor nuclear translocator subunits. The prognostic relevance of HIF-1α protein overexpression has been shown in breast cancer. The impact of HIF-1α alternative splice variant

Therefore, Dales et al. [39] investigated the prognostic value of different HIF-1α transcript expression levels in breast cancer and found a significant relationship between either clinicopathological characteristics or patient metastasis-free survival. They proved mRNA expression of a *HIF-1αTAG*splice variant reflects a stage of breast cancer progression and is associated

Due to the fact that TNBC frequently shows morphologic evidence of hypoxia (central fibrosis and necrosis) [40, 41] an augmented expression of HIF-1α in tumors with a triple-negative phenotype should be anticipated. In fact, this had been elegantly demonstrated through the preferential expression of HIF-1α in peri-necrotic tumor cells in TNBC and BRCA1 mutated

In contrast, Tan et al. [43] and Choi et al. [44] demonstrated in TNBC an increase of carbonic anhydrase IX, a downstream product of the hypoxic pathway, rather than an increase in HIF-1α per se. The authors did not dispute the likely contribution of hypoxia to the tumors'

HIF-1α overexpression is an indicator of poor prognosis and significant survival time reduction in patients suffering from breast cancer [45]. HIF-1 upregulates transcription of angiogenic genes like erythropoietin (EPO) and vascular endothelial growth factor (VEGF), which induce sprouting of new vessels and in result they increase the risk of metastasis because they boost surface of contact between tumor cells and vasculature. HIF-1 induces transcription of cytoprotective proteins in malignant cells in hypoxic conditions. HIF-1α predicts poor prog-

The relationship between inflammation and tumor progression is widely accepted. This phenomenon is also well known in breast cancer, and is mediated by numerous interleukins.

expression on breast cancer prognosis in terms of metastasis risk is not well known.

and breast cancer among them.

and formation of a metastatic lesion [38].

with a worse prognosis [39].

breast cancers [42].

aggressive phenotype.

nosis breast cancer [46, 47].

#### **4.6. Androgen-targeted therapy**

TNBCs expressing the androgen receptor (AR-positive) account for about 10% of all TNBCs and are characterized by a more benign course [13]. These tumors express the AR, which can be detected by immunohistochemistry or the analysis of AR gene expression. AR-positive TNBCs have several common features with ER-positive breast tumors, including the expression of several estrogen-dependent genes and the frequent presence of PIK3CA mutations. Anti-androgens have been studied as potential drugs for these cancers. Few TNBCs express AR, and patients with AR-positive tumors were qualified for clinical trials with anti-androgens. Many molecules have been studied, but data on bicalutamide and enzalutamide are most extensive. Unfortunately, few patients responded to the treatment with these agents. Nonetheless, 20–35% of patients achieved disease stabilization [36]. It remains unclear whether these findings reflect the relatively mild nature of AR-positive TNBCs or whether they reflect the actual, but limited, activity of anti-androgens.

#### **4.7. Other agents**

New treatment targets for patients with cancer are being studied. These include, among others, reparixin (inhibitor of interleukin-8 activation of CXCR1/CXCR2 chemokine receptors), CXCR1/2 (stem cell pathway), cyclin-dependent kinases, c-Met pathway, aurora kinase inhibitor, death receptors, and CSF1 inhibitor (*colony stimulating factor 1*).

After over 20 years with relatively few new treatments for the TNBC, recent years have seen a growing interest in the TNBC among researchers. This is because more and more people with breast cancer have the TNBC, which is aggressive and tends to metastasize. Currently, studies are assessing different chemotherapy regimens and are testing the usefulness of new targeted therapies. In the early stages of the TNBC, standard neoadjuvant chemotherapy might save patients' lives; patients who receive standard neoadjuvant therapy can later receive adjuvant chemotherapy or be included in clinical trials if there is extensive residual cancer after neoadjuvant therapy. Growing evidence supports the benefit of adding cisplatin to the chemotherapy with taxanes/anthracyclines in patients with *BRCA* mutations [37].

Because many new targeted therapies for the TNBC are assessed in ongoing trials, we hope that the treatment of TNBC will soon be improved.
