Breast cancer development and progression: Risk factors, cancer stem cells, signaling pathways, genomics, and molecular pathogenesis

Abstract

As the most commonly occurring cancer in women worldwide, breast cancer poses a formidable public health challenge on a global scale. Breast cancer consists of a group of biologically and molecularly heterogeneous diseases originated from the breast. While the risk factors associated with this cancer varies with respect to other cancers, genetic predisposition, most notably mutations in BRCA1 or BRCA2 gene, is an important causative factor for this malignancy. Breast cancers can begin in different areas of the breast, such as the ducts, the lobules, or the tissue in between. Within the large group of diverse breast carcinomas, there are various denoted types of breast cancer based on their invasiveness relative to the primary tumor sites. It is important to distinguish between the various subtypes because they have different prognoses and treatment implications. As there are remarkable parallels between normal development and breast cancer progression at the molecular level, it has been postulated that breast cancer may be derived from mammary cancer stem cells. Normal breast development and mammary stem cells are regulated by several signaling pathways, such as estrogen receptors (ERs), HER2, and Wnt/β-catenin signaling pathways, which control stem cell proliferation, cell death, cell differentiation, and cell motility. Furthermore, emerging evidence indicates that epigenetic regulations and noncoding RNAs may play important roles in breast cancer development and may contribute to the heterogeneity and metastatic aspects of breast cancer, especially for triple-negative breast cancer. This review provides a comprehensive survey of the molecular, cellular and genetic aspects of breast cancer.

Keywords: BRCA1/2; Breast cancer; Cancer stem cells; Estrogen receptors; HER2; Noncoding RNAs; Triple-negative breast cancer; Tumor heterogeneity.

Figure 1

Anatomical and histologic origins of breast cancer. Most breast cancers arise from the lobules or the ducts of the breast. In some cases, the tumor infiltrates the skin or components of the chest wall such as the pectoralis muscles. The tumor cells also are capable of converting the microenvironment into a tumor-friendly state to promote their growth and expansion.

Figure 2

Mammary cell hierarchy and breast cancer stem cells. Mammary stem cells (MaSCs) are multipotent self-renewing cells of great importance in the development and replenishment of mammary glands, as well as having implications in cellular origin of breast cancer stem cells (BCSCs), which has been extensively traced using various methods using human and mice samples. Two models have been established to define the relationship between MaSCs and breast cancer.

Figure 3

ER signaling pathway. Breast cancer cells have relatively high ERα expression and low ERβ expression. These two types of nuclear hormone receptors form homo- or heterodimers upon ligand binding and translocate into the cell nucleus for transcriptional regulation, which is the main function of ERs. ER dimers bind to the ERE region of target genes and recruit co-regulators to achieve the regulation of transcriptional activity. Another mechanism by which ERs control the expression of target genes is acting as a co-regulator for other transcription factors.

Figure 4

HER2 signaling pathway. HER2 as well as the other members of the EGFR family are receptor tyrosine kinases which are located on the cell membrane and responds to a wide variety of ligands. Phosphorylation of the tyrosine kinase domain in the cytoplasm initiates downstream oncogenic signaling pathways such as PI3K/AKT pathway and Ras/MAPK pathway.

Figure 5

Canonical Wnt/β-catenin signaling pathway. Canonical Wnt signaling plays significant roles in many biological and pathological processes such as mammary gland development and breast tumorigenesis. Wnt ligands bind with membrane receptors frizzled and LRPs, attenuating the ubiquitination of β-catenin by β-TrCP. Accumulation of β-catenin allows for nucleus translocation and downstream transcriptional activation. Inhibitors of Wnt signaling such as DKKs and SFRPs function as tumor suppressors by contributing to the degradation of β-catenin, thus impeding the transcription of β-catenin-targeting oncogenes.