The Overview of Breast Cancer: Related Signaling Pathways, Therapeutic Targets


View:374 Time:2018-08-14


Breast cancer is a cancer that develops in the tissues of breasts. Symptoms of breast cancer usually include a lump in the breast, a change in breast shape, dimpling of the skin, fluid coming from the nipple, a newly inverted nipple, or a red or scaly patch of skin. Among them, the first sign of breast cancer often is a breast lump or an abnormal mammogram in breast. Breast cancer starts when cells in the breast begin to grow out of control. These cells usually form a tumor that can often be seen on an x-ray or felt as a lump. If the cells can invade surrounding tissues or spread to distant areas of the body, the tumor is malignant. Breast cancer occurs almost entirely in women, but men can get breast cancer, too. In the recent decades years, breast cancer prevalence and mortality are still on the rise, meanwhile, the studies of breast cancer is hot in Clinical research and basic research. In this review, we summarize breast cancer-related signaling pathways and hotspot therapeutic targets, and hope that can give your research a hand.

1. The Common Types of The Breast Cancer

Breast cancers can start from different parts of the breast. Based on the different parts of the breast, breast cancer is divided into several types. Among them, the more common types are ductal cancers (breast cancers begin in the ducts that carry milk to the nipple) and lobular cancers (some start in the glands that make breast milk). There are also other types of breast cancer which based on Histochemistry, including inflammatory breast cancer, invasive breast cancer, et al. Besides that, therapeutically, it is subclassified into three groups: estrogen receptor (ER) positive, HER2 positive (amplified for the ERBB2 gene), and ER negative or triple negative.

2. Related Signaling Pathways in Breast Cancer

General speaking, signal transduction is critical in the development and treatment of cancer. Together with recent research, we have summarized the signaling pathways associated with breast cancer.

NF-κB Signaling Pathway and Breast Cancer

Nuclear factor kappa-light-chain-enhancer of activated B cells, also known as nuclear factor-kappa B (NF-kB), is a heterodimeric DNA-binding protein that consists of two major subunits, p50 and p65. NF-κB is widely used by eukaryotic cells as a regulator of genes that control cell proliferation and cell survival. In cancer, the crucial regulator proteins of NF-κB signaling pathway are mutated or aberrantly expressed, leading to defective coordination between the malignant cell and the rest of the organism. This is evident both in metastasis, as well as in the inefficient eradication of the tumor by the immune system[1]. Activated NF-kB can bind to DNA and lead to the expression of diverse genes that promote cell proliferation, regulate apoptosis, facilitate angiogenesis and stimulate invasion and metastasis[2][3][4]. Accumulating evidence show that NF-κB activity is commonly elevated in breast cancer. For instance, H Nakshatri, et al. reported that NF-kappaB was constitutively active in ER-negative breast cancer cell lines in 1997[5]. Furthermore, NF-κB recently becomes a key target to breast cance treatment. Jisheng Xiao, et al. demonstrated that blocking the NF-kB signaling pathway can inhibit metastasis and growth of breast cancer via using bioreducible PEI-based/p65 shRNA complex nanoparticles[6]. Besides that, several studies also suggest that the NF-κB signaling pathway can become a treatment target of breast cancer[7][8].

TGF-beta Signaling Pathway and Breast Cancer

The transforming growth factor beta (TGFβ) signaling pathway, also known as TGFβ signaling pathway, is involved in many cellular processes including cell growth, cell differentiation, apoptosis, cellular homeostasis and other cellular functions. The TGF-β ligands have three described isoforms; TGF-β1, TGF-β-2, and TGF-β-3. TGF-β plays a dual role in cancer development as it displays both tumorigenic and tumor-suppressive effects. TGF-β has been reported to act as a tumor suppressor by inhibiting the cell proliferation of breast cancer cell lines[9]. In the research of E. M. de Kruijf, et al., they have demonstrated that the combination of TGF-β pathway biomarkers can provide valuable prognostic value for breast cancer patients. Stratifying tumors according to the low or high expression of TGF-β biomarkers had strong prognostic implications in our patient population. Additionally, their results highlight the importance of accounting for protein expression levels and the complex interactions taking place between components with the TGF-β pathway[10].

PI3/AKT/mTOR Signaling Pathway and Breast Cancer

The PI3K/AKT/mTOR pathway is an intracellular signaling pathway important in regulating the cell cycle and is directly related to cellular quiescence, proliferation, cancer, and longevity. PI3K activation phosphorylates and activates AKT, localizing it in the plasma membrane[11]. The signaling pathway is activated by stimulation of receptor tyrosine kinases, which in turn trigger PI3K activation, followed by phosphorylation of AKT and mTOR complex 1 (mTORC1). In various subtypes of breast cancer, aberrations in the PI3K/AKT/mTOR pathway are the most common genomic abnormalities, including the PIK3CA gene mutation, the loss-of-function mutations or epigenetic silencing of phosphatase, tensin homologue (PTEN), et al[12][13]. Triple-negative breast cancer (TNBC) is defned by the absence of targetable aberrations, such as hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2). In TNBC, oncogenic activation of the PI3K/AKT/mTOR pathway can happen as a function of overexpression of upstream regulators (e.g., epidermal growth factor receptor [EGFR]), activating mutations of PI3K catalytic subunit α (PIK3CA), loss of function or expression of phosphatase and tensin homolog (PTEN), and the proline-rich inositol polyphosphatase, which are downregulators of PI3K[14][15][16]. Recently, emerging preclinical data support the notion that aberrations in the PI3K/AKT/mTOR pathway predict TNBC inhibition by targeted agents[17]. If you want to get more information about the treatment target of PI3K/AKT/mTOR pathway in breast cancer, please click here to view the related article. If you can't see the full text, please contact us via the live chat in the page of lower right.

Notch Signaling Pathway and Breast Cancer

The Notch signaling pathway is a highly conserved, intercellular signaling mechanism essential for proper embryonic development in all metazoan organisms. Mammals possess four different notch receptors (NOTCH1, NOTCH2, NOTCH3, and NOTCH4). Accumulating studies in primary human breast cancer have shown that high-level expression of Jag1 (Jag1High) or Notch1 (Notch1High) mRNA in tumors correlates with poor outcome and is an independent prognostic indicator[18][19]. Emerging evidence has demonstrated that the oncogenic role of Notch in breast cancer is mediated in part via its crosstalk with other signaling pathways, such as the estrogen pathway. Approximately 80% of breast cancers express the estrogen receptor and are treated with anti-estrogens, but resistance to anti-estrogens often develops. One mechanism of resistance may be via the Notch pathway[20]. From a therapeutic standpoint, concurrently targeting both the estrogen receptor and the notch pathway may help to overcome or at least in part delay this resistance.

Several Studies of Other Signaling Pathway in Breast Cancer

In 2011, Mamiko Shimizu, et al. reported that Notch knockdown reduced transcription of uPA and phenocopied uPA knockdown in breast cancer cells. Moreover, the data of their research suggested that JAG1-induced Notch activation results in breast cancer progression by upregulation of the plasminogen activator system, directly linking these 2 important pathways of poor prognosis. Please click here to to view the related article. If you can't see the full text, please contact us via the live chat in the page of lower right.

In addition, Lauren L.C. Marotta, et al. found that the IL-6/JAK2/Stat3 pathway was preferentially active in CD44+CD24- breast cancer cells compared with other tumor cell types, and inhibition of JAK2 decreased their number and blocked growth of xenografts. Furthermore, their results highlight the differences between distinct breast cancer cell types and identify targets such as JAK2 and Stat3 that may lead to more specific and effective breast cancer therapies. Please click here to view the reference. to view the related article. If you can't see the full text, please contact us via the live chat in the page of lower right.

Furthermore, Perrin F. Windham from University of Montevallo found that the cGMP signaling pathway may be aberrantly regulated in breast cancer and can be a target for the prevention and treatment of breast cancer. Please click here to view the reference. to view the related article. If you can't see the full text, please contact us via the live chat in the page of lower right.

This year, Chien-Wei Tseng, from China Medical University, demonstrated that transketolase regulates the metabolic switch to control breast cancer cell metastasis via the alpha-ketoglutarate signaling pathway and can be exploited as a modality for improving therapy. Please click here to view the reference. to view the related article. If you can't see the full text, please contact us via the live chat in the page of lower right.

3. The Most Popular Targets in Breast Cancer Treatment

As you known, breast cancer is the most common female cancer in the world, the second leading cause of cancer death after lung cancer, and the main cause of death in women aged 20 to 59. With the further study of breast cancer mechanism, the target of breast cancer treatment has been gradually found.

HER2 for The Treatment of Breast Cancer

HER2 (also known as ERBB2), a member of the HER family of tyrosine kinase receptors (HER1–4), is an essential breast cancer oncogene. Emerging evidence founded that a significant correlation exists between ERBB2 overexpression and reduced survival of breast cancer patients, and amplification of ERBB2 occurs in 30% of early-stage breast cancers[21]. Treatment with the anti-HER2 monoclonal antibody trastuzumab has revolutionized the outcome of patients with this aggressive breast cancer subtype, but intrinsic and acquired resistance is common. With the further study of breast cancer mechanism, growing understanding of the biology and complexity of the HER2 signaling network and of potential resistance mechanisms has guided the development of new HER2-targeted agents. Combinations of these drugs to more completely inhibit the HER receptor layer, or combining HER2-targeted agents with agents that target downstream signaling, alternative pathways, or components of the host immune system, are being vigorously investigated in the preclinical and clinical settings[22]. As shown in the figure 1, the HER2 network and HER2-targeted therapy for HER2+ breast cancer.

Androgen Receptor for The Treatment of Breast Cancer

Androgen receptor (AR) is a steroid hormonal receptor that belongs to the nuclear receptors family together with estrogen (ER), progesterone (PR), glucocorticoid and mineralcorticoid receptor. Recent data suggest that triple negative breast cancer (TNBC) is not a single disease, but it is rather an umbrella for different ontology-profiles such as mesenchymal, basal like 1 and 2, and the luminal androgen receptor (LAR). The LAR subtype is characterized by the expression of the Androgen Receptor (AR) and its downstream effects. Notwithstanding the role of the AR in several signaling pathways, its impact on a biological and clinical standpoint is still controversial. The LAR subtype has been associated with better prognosis, less chemotherapy responsiveness and lower pathologic complete response after neoadjuvant treatment. Clinical evidence suggests a role for anti-androgen therapies such as bicalutamide, enzalutamide and abiraterone, offering an interesting chemo-free alternative for chemo-unresponsive patients, and therefore potentially shifting current treatment strategies[23].

Beside the two targets, there are still several targets for treatment of breast cancer, such as The CXCL12-CXCR4 chemotactic pathway, Adipose tissue, EP4, et al. These targets not only are genes, but also are tissue or signaling pathway. Despite our remarkable success in breast cancer research, there is still a long way to go to study the mechanism of breast cancer.

References

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