**3.2. Molecular classification**

**3. Classification of breast cancer**

Breast cancer can be broadly classified based on the location and aggressiveness of the disease. Two main classes of breast cancer are in situ carcinoma and invasive (infiltrating) carcinoma. Breast carcinoma in situ can be divided into two types. Ductal carcinoma in situ (DCIS) originates from the cells lining the ducts that transport milk to the nipple while lobular carcinoma in situ (LCIS) occurs in the cells of lobules, the milk-producing glands at the end of breast ducts [3, 7]. Both DCIS and LCIS are premalignant lesions that do not invade deeper or spread through the body. Women with these lesions have higher likelihood of getting cured but also have increased risk of developing invasive breast cancer in the future. DCIS is significantly more common accounting for 80–90%, while LCIS accounts for 10–20% of breast cancer cases [3]. DCIS has been traditionally sub-classified to five well-recognized subtypes as Solid, Papillary, Micropapillary, Cribriform and Comedo based on the architectural features of the tumor [8]. Invasive carcinomas, similar to in situ carcinomas are differentiated into histological subtypes. These subtypes include infiltrating

**Figure 1.** Histological classification of breast cancer subtypes. Modified from Malhotra et al., 2010 [7].

**3.1. Histopathological classification**

106 Breast Cancer and Surgery

Breast cancer is a heterogeneous disease with diverse histological and molecular variations determining the biological behavior and therapeutic response. The occurrence as well as death due to breast cancer is on the rise globally despite advances in the development of diagnostic techniques and medications. There are many factors including age, family history, receptor status and others that have been investigated to assess patients' risk and treatment selection. It has been proven that receptor status is the most valuable in determining prognosis and responsiveness to therapy [11, 12]. Based on the receptor status, breast cancers are divided into three main groups. The first group includes estrogen receptor (ER) or progesterone receptor (PR) positive, while the second group comprises tumors that tested positive for human epidermal growth factor receptor 2 (HER2) with or without ER and PR positivity. Finally, triple-negative breast cancer (TNBC) is defined by the absence of ER/ PR expression and HER2 amplification [11]. Targeted therapy is available for breast cancer patients that express ER, PR or HER2 receptors; however, no standard treatment options are in practice for TNBC patients. Traditional chemotherapeutic regimens are utilized for this type of patients [13].

A number of techniques including immunohistochemistry (IHC), DNA microarray technology, fluorescent in situ hybridization (FISH) are utilized to reveal molecular differences within the same or different histopathological specimens [14–16]. Using IHC and DNA microarrays lead to the identification of five discrete subtypes of breast cancer. These subtypes include luminal A (ER<sup>+</sup> and/or PR<sup>+</sup> and HER2<sup>−</sup> ), luminal B (ER<sup>+</sup> and/or PR <sup>+</sup> and HER2+ ), HER2 overexpressing (ER− and PR<sup>−</sup> , HER2<sup>+</sup> ), basal-like (ER− /PR− /HER2− , cytokeratin 5<sup>+</sup> /6<sup>+</sup> and/or epidermal growth factor receptor (EGFR)<sup>+</sup> ) and normal breast-like. These different breast cancer subtypes are diverse in prognosis and therapeutic management [11]. Microarray classification of breast cancer is represented in **Table 2**. This classification is based on two types of epithelial cells including luminal and basal cells (and/or myoepithelial) in human mammary gland. These cells can be identified using IHC technique as luminal cells express ER and PR receptors and keratins 8<sup>+</sup> /18<sup>+</sup> , whereas basal cells are keratins 5<sup>+</sup> /6<sup>+</sup> and 17<sup>+</sup> [17, 18].On the other hand, TNBC can be identified by ER− , PR− and HER2<sup>−</sup> using IHC range between 0 and 1 or by FISH negative if 2+ on IHC [15].

Various receptors including estrogen receptor (ER) and other growth factor receptor signaling pathways play an important role in breast cancer initiation and progression. Targeting these receptors by specific inhibitors may lead to the inhibition of tumor growth [20].


**4. Breast cancer receptors (ER, PR and HER2) and their involvement** 

Despite the fact that a large number of potentially valuable factors have been identified, only three receptors, the estrogen receptor-alpha (ER*α*), the progesterone receptor (PgR), and the HER2 are utilized in clinical practice, and their assessment is obligatory [21]. Approximately 70% of all breast cancers, which belong to the molecular subtypes luminal A or luminal B, express ER*α*. There is strong evidence demonstrating that estrogen plays an important role in the progression and development of breast cancers, although the causes behind these malignancies still remains uncertain [22]. ER alpha positive breast cancers depend on estrogen signaling for proliferation. Binding of estrogen to ERs leads to dimerization of the receptor which then translocates to the nucleus and binds estrogen response elements in the DNA sequence. This leads to cell proliferation as a result of stimulation of target genes [23]. ER*α* mediates a number of molecular signaling such as mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways which are involved in cell growth

Endocrine and Cell Surface Receptor Signaling in Breast Carcinogenesis

http://dx.doi.org/10.5772/intechopen.74679

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**Figure 2.** The PI3K/AKT/mTOR and the RAS/RAF/MEK/MAPK pathways. Modified from Toss and Cristofanilli [25].

**in cancer progression**

**4.1. Estrogen receptor (ER)**

and proliferation [24] as can be seen in **Figure 2**.

IHC, immunohistochemistry; ER, estrogen receptor; PgR, progesterone receptor, +, positive, − negative.

**Table 2.** Microarray classification of breast cancer [19].
