**1.1. Cell subtypes in human breast cancer and the alterations in calcium homeostasis**

The mammary gland is an exocrine, compound tubuloalveolar gland [2]. Each mammary gland has 15–20 glandular lobes in its structure, each lobe being a separate gland with its excretory channel (galactophore channel) that opens at the level of the nipple via the galactophore pore [3]. The glandular lobe consists of glandular lobules delimited by fibrous connective tissue and fat. Lobules have a radiant arrangement, each opening through a lactiferous duct in the nipple, presenting a dilation called lactiferous sinus before opening. Lobules are composed of parenchyma and stroma, and made of loose connective tissue [4]. Each lobule consists of alveoli, lined by cuboidal epithelial cells, which secrete milk, and lactiferous ducts, lined by columnar epithelium, both epithelia surrounded by an outer layer of myoepithelial cells. The stromal cell population is composed of mesenchymal cells, including adipocytes, fibroblasts, and immune cells.

very helpful for the further detection and characterization of signal transduction pathways such as the Notch, Wnt, and Hedgehog pathways that may be crucial for the self-renewal and

Alterations in Calcium Signaling Pathways in Breast Cancer

http://dx.doi.org/10.5772/intechopen.80811

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Identification of breast cancer stem cells is strictly dependent on cell-surface markers. Several markers have been proposed such as hyaluronan receptor (CD44), signal transducer CD24 (CD24), CD133 (Prominin-1), integrins CD29 (β1) and CD49f (α6), aldehyde dehydrogenase-1 (ALDH1), as tumor-initiating cells in breast cancer progression with high metastatic potential and in high-grade tumors resistant to therapeutic treatments [14–17]. However, currently, there is no agreement regarding the phenotypic characterization of breast cancer stem cells. In addition to this discord, the great heterogeneity of breast tumors reflected by a myriad of histological subtypes with variable clinical presentations and diverse molecular signatures also contributes to this major shortcoming. The intrinsic molecular taxonomy describes five major subtypes of breast cancer (luminal-A, luminal-B, basal-like, HER2, and normal-like) which overlap with various clinicopathological classification systems and correlate with clinical behavior being vital for patient's management. In addition, different breast cancer stem cells phenotypes have been described contributing to the proper characterization and nomenclature of breast malignant lesions. Several immunohistochemical markers have been characterized showing that the

prevalence of stem cell-like markers varies according to tumor histological subtype [18].

In the light of these facts, some studies have proposed ALDH1 as an independent prognostic marker in breast cancer. Ginestier et al. showed a prevalence of 30% for ALDH1 positivity in a cohort comprising 577 breast tumors from two independent tumor sets. They also showed that ALDH1 expression correlates with a high histological grade, human epidermal growth factor receptor type 2 (HER2) overexpression, and absence of estrogen receptor and progesterone receptor expression [19]. A similar study [20] highlighted the worst prognosis of breast cancer patients with ALDH1 expression. There is no agreement in this matter, as other studies fail to find these correlations [21] even in more aggressive breast tumor subtypes such as

With all these conflicting results, the reliability of ALDH1 expression as a clinical prognostic factor is doubtful, thus increasing the need for a standard protocol and more rigorous evaluation criteria, as well as consideration of the dissimilarity between whole-tissue staining versus

Alterations in calcium homeostasis frequently occur in some pathological conditions such as malignant proliferation and could have a key role to play in the near future of some targeted therapeutic approaches. Some recent studies have shown that exposure of breast cancer cells to chemotherapy (i.e., carboplatin) induces Ca2+ release and leads to an enrichment of breast cancer stem cells [23]. Lu et al. have documented that chemotherapy induces the expression of glutathione S-transferase omega 1 (GSTO1), a factor which is dependent on hypoxia-inducible factor 1 (HIF-1) and HIF-2. In turn, low level of GSTO1 revokes carboplatin-induced breast cancer stem cell enrichment, decreasing tumor initiation and metastatic potential and delaying tumor recurrence after chemotherapy. The authors also found that GSTO1 interacts with the ryanodine receptor (RYR1) and increases calcium release from the endoplasmic reticulum. In this manner, high levels of cytosolic calcium activate proline-rich tyrosine kinase 2 (PYK2)/ tyrosine-protein kinase (SRC)/signal transducers and activators of transcription factors 3

fate determination of MSCs.

inflammatory breast cancer.

tissue microarray staining [22].
