**1. Introduction**

Breast cancer is the most common cancer in women [1], and it comprises heterogeneous tumors with different biological features, clinical course, prognosis, and response to treatment [2].

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

With modern techniques, we can distinguish many molecular forms of breast cancer [3], which is important because the molecular classification of breast cancer enables effective, individualized treatment [4]. Based on cDNA microarray and immunohistochemical analysis, five basic molecular subtypes of breast cancer have been distinguished:

The TNBC has an aggressive course, grows fast, and metastasizes early, usually to the brain and lungs, and less commonly to the bones and liver. Compared with other breast cancers, the TNBC is poorly differentiated (G3) in the Bloom-Richardson classification [5, 6, 9]. In 2010, studies among 15,240 women with breast cancer, including 2500 with the TNBC, showed that

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

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The TNBC is also characterized by early recurrence, usually within 1–3 years after diagnosis [8]. Most patients with TNBCs have a poor prognosis because adjuvant therapy rarely leads to remission, and the presence of metastases is associated with a high resistance to chemotherapy and short survival [9]. Not all patients with TNBC, however, have a poor prognosis [6, 7, 9]. Numerous studies showed that the TNBC is related to the dysfunction of the *BRCA* genes and their protein products [9, 10]. According to Atchley et al. [10], TNBCs occur in 57% of patients with breast cancer and *BRCA1* mutations. Moreover, more than a half of TNBCs overexpress the MGFR receptor (c-Met growth factor receptor), which is associated with the signaling pathway initiating the epithelial-mesenchymal transformation [8, 9]. The TNBC is often associated with *P53* mutations, PTEN loss, activation of the PI3K/AKT signaling pathway, and loss of heterozygosity of the loci4p14, 4p15.3 m 5q11.1,

Although TNBC was initially detected in basal-like carcinoma, these two types of breast cancer are different from each other [12]. The basal-like carcinoma is diagnosed based on the immunohistochemical status of steroid receptors (ER, PR) and the HER2 receptor [4, 7, 9].

Molecularly, the TNBC comprises a heterogeneous group of tumors. Lehmann et al. [13] dis-

Of all these TNBC subtypes, only the LAR TNBC does not express basal cytokeratins, such as CK5, CK6A, CK6B, CK14, CK16, CK17, CK23, and CK81, and it does not express proteins such as EGFR, p53, smooth muscle actin, P-cadherin, and c-Kit receptor [10, 11]. In contrast, the LAR TNBC expresses CK7, CK8, CK18, CK19, and the androgen receptor [12]. Moreover, the LAR TNBC expresses genes whose protein products regulate hormonal pathways and the

The BL1 TNBC expresses genes whose protein products are associated with cell cycle regula-

The BL2 TNBC expresses genes whose protein products are involved in the signal transduction in the cell, through growth factors such as EGF, NGF, MET, Wnt/β-catenin, and IGF1R [12].

patients with the TNBC had a worse prognosis than other patients [5, 6, 8–10].

5q14, and 18q22–23 [11].

tinguished six types of the TNBC:

• immunomodulatory (IM)

• mesenchymal stem-like (MSL)

• luminal androgen receptor (LAR)

• mesenchymal (M)

• unstable

• basal-like 1 and basal-like 2 (BL1 and BL2)

gene for the androgen receptor and its co-activators [12, 13].

tion, cell proliferation, repair process, and DNA replication [12].


On routine histology, breast cancer is defined based on immunohistochemical detection of three receptor proteins: estrogen receptor (ER), progesterone receptor (PR), and HER2 receptor with additional gene status analysis of the *HER2* gene (*in situ* hybridization). This immunohistochemical profiling shows that 25% of breast cancers consist of type A luminal cells; 32%, of type B/HER2− cells; 18.5%, of luminal B/HER+ cells; and 7%, of cells that express solely the HER2 protein [7]. Cancers of the luminal subtype A and B express genes characteristic for glandular cells, which form the inner layer of normal ducts and lobules of the breast. Moreover, the luminal subtypes of breast cancer express cytokeratins typical for glandular cells, such as cytokeratins 8, 18, and 19, as well as α 6 integrins and Bcl-2, Ep-CAM, and MUC1 proteins. The luminal subtype A is characterized by a high expression of genes for estrogen receptors and progesterone receptors and genes regulating the function of these receptors, i.e., *FOX1*, *GATA3*, *LIV-*1, and *XBP1*. The luminal subtype A breast cancer typically occurs in young patients; in contrast to the luminal subtype B, the luminal subtype A breast cancer has a good prognosis [8–10]. In recent years, among all the molecular subtypes of breast cancer, the triple-negative breast cancer (TNBC) has been studied most extensively.
