Molecular Portrait of the Normal Human Breast Tissue and Its Influence on Breast Carcinogenesis

Abstract

Normal human breast tissue consists of epithelial and nonepithelial cells with different molecular profiles and differentiation grades. This molecular heterogeneity is known to yield abnormal clones that may contribute to the development of breast carcinomas. Stem cells that are found in developing and mature breast tissue are either positive or negative for cytokeratin 19 depending on their subtype. These cells are able to generate carcinogenesis along with mature cells. However, scientific data remains controversial regarding the monoclonal or polyclonal origin of breast carcinomas. The majority of breast carcinomas originate from epithelial cells that normally express BRCA1. The consecutive loss of the BRCA1 gene leads to various abnormalities in epithelial cells. Normal breast epithelial cells also express hypoxia inducible factor (HIF) 1α and HIF-2α that are associated with a high metastatic rate and a poor prognosis for malignant lesions. The nuclear expression of estrogen receptor (ER) and progesterone receptor (PR) in normal human breast tissue is maintained in malignant tissue as well. Several controversies regarding the ability of ER and PR status to predict breast cancer outcome remain. Both ER and PR act as modulators of cell activity in normal human breast tissue. Ki-67 positivity is strongly correlated with tumor grade although its specific role in applied therapy requires further studies. Human epidermal growth factor receptor 2 (HER2) oncoprotein is less expressed in normal human breast specimens but is highly expressed in certain malignant lesions of the breast. Unlike HER2, epidermal growth factor receptor expression is similar in both normal and malignant tissues. Molecular heterogeneity is not only found in breast carcinomas but also in normal breast tissue. Therefore, the molecular mapping of normal human breast tissue might represent a key research area to fully elucidate the mechanisms of breast carcinogenesis.

Exposure to EGF and 17β‑estradiol irreversibly affects the proliferation and transformation of MCF7 cells but is not sufficient to promote tumor growth in a xenograft mouse model upon withdrawal of exposure

“…In HER2-transformed cells, TGFβ further stimulated HER2 signaling to promote malignancy and induced resistance to anti-HER2 therapy. The observations in the present study showed changes in cellular responsiveness, and confirmed the previously reported promotion of transformation by EGF and TGFβ1, the stimulatory effect of 17β-estradiol, and the inhibitory effects of Iressa and tamoxifen (3)(4)(5)(6)(7)(8)43,44). The observations also confirmed that long-term exposure may contribute to the development of resistance to Iressa in 17β-estradiol-exposed cells, and to SB431542 in EGF-and/or 17β-estradiol-exposed cells.…”

“…EGF and 17β-estradiol are known stimulators of cell proliferation (3)(4)(5)(6)(7)(8)(9). The present study observed that prolonged exposure resulted in faster proliferation of McF7 cells, and this higher rate of proliferation was maintained even upon removal of EGF and 17β-estradiol from the medium (Fig.…”

“…Tumorigenesis is a complex process involving alterations of multiple genes, proteins and regulatory pathways (6,7). In breast cancer, the overexpression of epidermal growth factor receptor (EGFR) in the primary tumor correlates with increased metastatic dissemination and aggressive tumor progression (8).…”

Microvessel Density and Mammaglobin A Expression as Prognostic Markers in Molecular Types of Breast Cancer

“…Unlike MGB, MVD count is not restricted to the malignantly transformed breast tissue, its use being extended to a wide range of human benign and malignant conditions. MGB is one of the markers of the normal and malignantly transformed breast tissue where it can be detected in two main forms with different molecular masses [1,2]. When investigating the human MGB gene, in 1998, Watson et al [3] have concluded that it is not ver y well conserved phylogenetically and it presents a series of architectural similarities with uteroglobin genes and rat prostatein subunits.…”

“…Using fluorescent in situ hybridization, the MGB gene has been localized on chromosome 11q13 which is usually amplified in breast cancer [3]. Increased MGB protein expression in breast cancer patients is associated with a favorable prognosis although its implications and functions are not yet fully understood [1,4]. MGB-A, one of the members of the secretoglobin superfamily, is expressed in most breast cancer cells and is currently being studied as a potential therapeutic target in immune therapies [5].…”