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.

BackgroundBreast cancer (BrCa) is a complex disease driven by aberrant gene alterations and environmental factors. Recent studies reveal that abnormal epigenetic gene regulation also plays an important role in its pathogenesis. Ubiquitin carboxyl- terminal esterase L1 (UCHL1) is a tumor suppressor silenced by promoter methylation in multiple cancers, but its role and alterations in breast tumorigenesis remain unclear.Methodology/Principal FindingsWe found that UCHL1 was frequently downregulated or silenced in breast cancer cell lines and tumor tissues, but readily expressed in normal breast tissues and mammary epithelial cells. Promoter methylation of UCHL1 was detected in 9 of 10 breast cancer cell lines (90%) and 53 of 66 (80%) primary tumors, but rarely in normal breast tissues, which was statistically correlated with advanced clinical stage and progesterone receptor status. Pharmacologic demethylation reactivated UCHL1 expression along with concomitant promoter demethylation. Ectopic expression of UCHL1 significantly suppressed the colony formation and proliferation of breast tumor cells, through inducing G0/G1 cell cycle arrest and apoptosis. Subcellular localization study showed that UCHL1 increased cytoplasmic abundance of p53. We further found that UCHL1 induced p53 accumulation and reduced MDM2 protein level, and subsequently upregulated the expression of p21, as well as cleavage of caspase3 and PARP, but not in catalytic mutant UCHL1 C90S-expressed cells.Conclusions/SignificanceUCHL1 exerts its tumor suppressive functions by inducing G0/G1cell cycle arrest and apoptosis in breast tumorigenesis, requiring its deubiquitinase activity. Its frequent silencing by promoter CpG methylation may serve as a potential tumor marker for breast cancer.

We have investigated some roles of splicing factor polypyrimidine tract-binding protein (PTBP1) in human breast cancer. We found that PTBP1 was upregulated in progressively transformed human mammary epithelial cells (HMECs), as well as in breast tumor cell lines compared with HMECs with finite growth potential and found that the level of PTBP1 correlated with the transformation state of HMECs. Knockdown of PTBP1 expression substantially inhibited tumor cell growth, colony formation in soft agar and in vitro invasiveness of breast cancer cell lines, a result similar to what we have reported in ovarian cancer. However, ectopic expression of PTBP1 (as a PTBP1–EGFP fusion protein) did not enhance the proliferation of immortalized HMEC. Rather, PTBP1 expression promoted anchorage-independent growth of an immortalized HMEC as assessed by increased colony formation in soft agar. In addition, we found that knockdown of PTBP1 expression led to upregulation of the expression of the M1 isoform of pyruvate kinase (PKM1) and increase of the ratio of PKM1 vs PKM2. PKM1 has been reported to promote oxidative phosphorylation and reduce tumorigenesis. Correspondingly, we observed increased oxygen consumption in PTBP1-knockdown breast cancer cells. Together, these results suggest that PTBP1 is associated with breast tumorigenesis and appears to be required for tumor cell growth and maintenance of transformed properties. PTBP1 exerts these effects, in part, by regulating the splicing of pyruvate kinase, and consequently alters glucose metabolism and contributes to the Warburg effect.