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REVIEW ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 12  |  Page : 937-941

PTEN and SHIP: Impact on lymphatic metastasis in breast cancer


1 Department of General Surgery, Hebei Yanda Hospital, Hebei, China
2 Department of General Surgery, Affliated Hospital of Taishan Medical University, Tai'an, China
3 Department of Gastroenterology, The Army General Hospital, Beijing, China
4 Department of Breast Surgery, Affliated Hospital of Taishan Medical University, Tai'an, China

Date of Web Publication11-Dec-2018

Correspondence Address:
Xiang-qi Li
Department of Breast Surgery, Affliated Hospital of Taishan Medical University, Tai'an 271000
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.193894

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 > Abstract 


Lymph node metastasis is the most common form of metastasis in breast cancer and a crucial indicator influencing breast cancer treatment results. The biological process of lymph node metastasis involves deficiency and mutation of tumor suppressor genes. PTEN and SHIP are critical indicators used to detect occurrence, development, invasion, and metastasis of breast cancer. Loss of expressions of PTEN and SHIP may contribute to lymphatic metastasis of breast cancer, so they can be used as objective indicators for judging the biological behavior of breast cancer. In this study, we perform a comprehensive analysis to investigate the effect of PTEN and SHIP gene expression on regulating lymph node metastasis in breast cancer.

Keywords: Breast cancer, gene expression, lymphatic metastasis, PTEN, SHIP


How to cite this article:
Li K, Li Gd, Sun Ly, Li Xq. PTEN and SHIP: Impact on lymphatic metastasis in breast cancer. J Can Res Ther 2018;14, Suppl S5:937-41

How to cite this URL:
Li K, Li Gd, Sun Ly, Li Xq. PTEN and SHIP: Impact on lymphatic metastasis in breast cancer. J Can Res Ther [serial online] 2018 [cited 2019 Oct 14];14:937-41. Available from: http://www.cancerjournal.net/text.asp?2018/14/12/937/193894




 > Introduction Top


The incidence of breast cancer has risen, and the age of onset tends to be earlier. Lymphatic metastasis is an important measurement for survival rates of patients during the transfer channel of breast cancer. Loss of tumor suppressor genes and mutation plays an important role in the process of lymphatic metastasis. Previous studies are mainly focused on effects of p53, p16, and p27 on breast cancer metastasis. Recently, it has been found that loss of tumor suppressor genes PTEN, SHIP play an important role in lymphatic metastasis of breast cancer, which should not be ignored. PTEN is found to be the most frequently mutated or missing tumor suppressor gene in human cancer cells after p53,[1] and SHIP plays a stronger role in migration of tumor cells than PTEN does. The expression of these two genes might be closely related to the tumor occurrence, development, metastasis, and invasion. Although studies on the two genes are not mature nowadays, it has already been verified preliminarily that the two genes have a high frequency of mutation or missing in several types of primary tumor,[2] which suggests that the lymphatic metastasis may be related to the loss expression of PTEN and SHIP.


 > The Biological Basis of Lymphatic Metastasis About Breast Cancer Top


The most common way of metastasis for breast cancer is lymphatic metastasis, which occurs earlier, and is also an important index to influence the clinical therapy. As the body's most important immune system, lymphatic system can do the job of immune surveillance and immune regulation, at the same time, the lymph circulation also can adjust to maintain homeostasis of the body and result in lymphatic metastasis of the tumor. Lymphatic metastasis of breast cancer is regulated by multigene expression and multiple signaling pathways, including a series of complex biological processes, such as the cell detachment, transference, and the growth of metastases. Tumor cells can fall off into the vascular system by breaching the membrane, which is the early metastasis of cancer, and lymphangiogenesis promotes lymphatic metastases. Cells invade lymphatic capillary by adhering, migrating, and then gather to form tumor emboli, developing lymphatic metastasis[3] by entering into the next level of lymph vessels and regional lymph nodes. It was ever believed that lymphatic metastasis is a passive process that detached cells arrive at regional nodes through the drainage of original local lymphatic. However, recent studies about lymphatic growth factor and lymphatic marker show that lymphatic endothelial cell and lymphangiogenesis exists in breast cancer stromal cells, lymphangiogenesis functions as a measurable bridge in the events of invasion, development, and metastasis. Lymphatic endothelial cells and tumor cells are correlative, under the mediation of relevant signaling pathways, they can promote the formation of lymphatic vessels and increase the density of lymphatic vessels, at the same time, destroy or change the structure and form of the original lymph vessel, which leads to lumen expansion and tube opening of microvessel and offers possible conditions to lymph vessel invasion.[4] Recent studies show that the formation of lymph vessel is not only focused on the cancer tissue and its surrounding, but also densely populated in the lymph nodes of tumor region, especially in the sentinel lymph node, and this phenomenon is so obviously occurred that it is considered lymphatic generated phenomenon.[5],[6] Moreover, the lymphatic metastasis of breast cancer is started with such biological processes as the generation of new lymph vessel and the increase of lymph.[7] Wissmann and Detmar[8] and other experts believe that lymph vessels may also be increased by induction from tumor cells, and the malignant tumor metastasis may occur as this process starts even before tumor invades sentinel node. A couple of other studies confirm that, in addition to the lymphangiogenesis, the transference and invasion of tumor are also affected by interstitial fluid flow, launching further tumor invasion and metastasis directly by the autologous chemotaxis mechanism.[9]

However, researchers have different understandings about lymphangiogenesis in tumor tissue and the function of lymph vessel in tumor peripheral. Animal experiments show that some lymphatic vessels lost the drainage function due to the extrusion of tissue, so it has no effect on the lymphatic metastasis, but peripheral lymphatic network can drain lymph from tumor. Compared with the lymphatic vessels within tumor, lymphatic vessels surrounding the tumor are more likely to mediate metastasis due to their larger quantity and irregular forms.[10] There is another possibility that the increasing of the tumor tissue fluid pressure and induction of lymphatic endothelial growth factor (vascular endothelial growth factor [VEGF]-C) expression makes peripheral lymphatic vessels intervene the process of lymphatic metastasis of tumor cells.[11],[12] Others found that lymph vessel is increasing in number around the solid tumor of such as breast cancer, cervical cancer, prostate cancer, but no lymphatic generating within tumor tissues.[13] However, in the animal model experiments, tumor lymphangiogenesis can be blocked by intervening in lymphatic growth factor expression, suggesting that expression of lymphatic vessel growth factors can promote the tumor lymphatic metastasis.[14],[15] These findings suggest that in the process of tumor metastasis, expression of lymphatic vessel growth factors and lymphangiogenesis plays an important role in controlling the spread of the tumor metastasis.[16] In conclusion, it differs greatly in different types of tumor lymphatic vessel formation and ways of lymphatic metastasis, and different research methods and standards also bring different results of the study, which remains to be studied in the further research.


 > The Structure and Function of Gene Pten and Ship Top


The tumor suppressor PTEN, with double phosphatase activity,[17] was discovered in 1997, and it is second high on mutation rate after the p53 gene in the human tumor. PTEN is closely related to the occurrence and development of a variety of human tumors, and the lack of it can lessen the regulation of cell growth and weaken controllability of cells apoptosis, adhesion, and migration.[18] The gene is located in chromosome 10 q23.3, including 9 exons, length of 1212 bp, and its transcript is 515 kb messenger RNA, the N-terminal of PTEN contains a nucleus or cytoplasm target area and a PIP2-binding motif, which is necessary for PTEN to perform its biological functions;[19] The protein tep1 produced by its coding is composed of 403 amino acids, locating in the cytoplasm, 122–133 amino acid sequence is core sequence which can be catalyzed by both the protein tyrosine phosphatases and the double specificity phosphatase. PTEN is the first ever found tumor suppressor genes with phosphatase and can influence protein phosphorylation by controlling tyrosine protein kinase produced by tumor gene in the cancer cells.[20]

Lipid phosphatase of PTEN protein can block phosphorylation of phosphatidylinositol 3 kinase (PI3K) acting on protein-serine/threonine kinase B (Akt) by the negative regulation of PI3K/Akt signal pathway, mediating cell proliferation, growth, survival and migration, to regulate the cell cycle, promote apoptosis, inhibit spread of detached tumor cells. If the PTEN expression or function was lost, sustainable phosphorylation of the PI3K/Akt can eventually lead to cells continuous division, volume enlargement, apoptosis retardation, and the formation of tumor blood vessels and lymphatic vessels. Protein PTEN may also selectively restrain activation of the RSA and extracellular regulating kinase (ERK) from the pathway of mitogen-activated protein kinase (MAPK), and inhibits phosphorylation of adaptor protein, regulate MAPK/ERK signal pathway negatively, ultimately have negative regulation on cell growth. Therefore, as a housekeeping gene which widely exists in the body's tissues, PTEN has a close relationship with tumor when it happens to detach, mutate, or express abnormally.

SHIP, the other member of inositol phosphatase family, was discovered after PTEN, and mainly expressed in hematopoietic cells,[21] including SHIP1, sSHIP, and SHIP2. SHIP gene is located in the chromosome 2 q36-2 q37, which contains a number of functional structure domain, and it can encode an approximately 145 kDa protein, whose N-terminal contains a homologous Src SH2 structure and C-terminal is comprised two NPXY amino acid sequences and a proline-rich region. The characteristic structure of SHIP can bond or interact with signal molecules (e.g., adapter proteins), portions of the immune receptor cytoplasmic domain, and other proteins. The SHIP protein also featured with 5' phosphatase activity can specifically hydrolyze PI-3, 4, 5-P3 into PI-3,4-P2. It can activate various signal transduction pathways as well as inhibit related signal transduction pathways by eliminating PI-3, 4, 5-P3.[22] As one of the members of inositol phosphatase family, SHIP2 plays an important biological role in the development of malignant tumors such as breast cancer in recent years.[23] Prasad et al.[24] found that, after SHIP2 protein expression is blocked, the proliferation in vitro and tumor growth in vivo and lung metastasis of breast cancer cell can slow down; If SHIP2 protein expression were raised in breast cancer cell lines, it can promote the activation of epidermal growth factor receptor-Akt signaling pathways and expression of chemotactic factor of CXCR4 and ability of tumor cells in vitro migration.[25] Therefore, the role of SHIP gene should not be ignored in breast cancer.


 > The Function of Pten, Ship Gene for Breast Cancer, and Lymphatic Metastasis Top


The occurrence, development, and metastasis of breast cancer are extremely complex, involving activation of related oncogene and inactivation of tumor-suppressor gene. Lymphatic metastasis is one of the important ways of the transference of breast cancer, whether the lymph node metastasis exists or not and the condition of the lymph node metastasis are important to estimate the prognosis of patients. PTEN is a tumor suppressor gene of double phosphatase activity, which can regulate PI3K/Akt pathway negatively, inactivation of PTEN, or decrease of protein expression can weaken intercellular adhesion ability, promote cancer cell invade the substrate.[26] Abnormal expression of PTEN in breast cancer is common, and gene inactivation has a certain relationship with the pathogenesis, invasion, metastasis, malignant transformation, unlimited growth, and clinical prognosis of breast cancer. It is mutated in a variety of tumors, which gives the breast cancer susceptibility. In the study of the biological behavior of breast cancer, PTEN protein is significantly high expressed in histological Grade 1 and Grade 2 breast cancer, but lowly expressed in histological grading level 3, thus the larger the primary tumor and the later clinical stage is, the lower the rate of PTEN expression is.[27] The loss expression of PTEN protein is common in estrogen receptor (ER) positive stage and the progressive stage of the axillary lymph node-negative breast cancer[28],[29] Some scholars think that Akt activation is positively correlated with the loss or overexpression of PTEN gene, and negatively correlated with intensity of progesterone receptor (PR) expression; If the loss of PTEN gene expression and its Her-2 expression appeared at the same time, it can strengthen the biological activity of Akt, which may lead to negative PR expression.[30] Study also found that if the PTEN is regarded as a judgment index of breast cancer prognosis, patients with higher expression have a significant high disease-free survival rate than those with lower expression and negative expression, and the prognosis is better when ER and PTEN expression appeared at the same time than those with only one expression or neither expression.[31],[32] Depowski et al.[33] indicated that positive expression rate of PTEN was obviously lower in patients with lymph node metastasis than that of those without lymph node metastasis, and positive expression rate of PTEN protein invasive in breast cancer was significantly lower than that in early invasive carcinoma. Di Cristofano and Pandolfi[34] have confirmed that PTEN protein positive expression is significantly reduced in breast cancer patients with lymph node metastasis and distant metastasis, so it can be said that the low expression of PTEN was a signal of breast cancer progression, the progressively low expression may be the symbol of late stage in the process of occurrence and development in breast cancer, and lack of PTEN expression can be an indication of poor prognosis in breast cancer.[35] Some other studies[36] show that lymphatic vessel density is closely related to the abnormal expression of VEGF-C in the stroma of breast cancer, suggesting that PTEN gene plays an extremely important role in the process of lymphatic vessel formation and metastasis in breast cancer. In the current study,[37] phosphorylation in PI3K/Akt pathway and aberration of PTEN gene widely exist in the process of lymphatic metastasis of breast cancer.

SHIP gene, as a member of the phosphoinositide lipid phosphatase family, is mainly expressed in hematopoietic cells, and it plays a negatively regulatory role in growth, differentiation and functional expression of hematopoietic cells, thus inhibiting cell survival and proliferation and promoting the apoptosis when it is excessively expressed.[38] The polymorphism of SHIP2 in the family is associated with the tendency of insulin resistance, however, SHIP1 control hematopoietic cell proliferation and mutation in some leukemia patients.[39] The SHIP is also involved in a signal pathway mediated by a variety of cytokines and growth factors and occurs tyrosine phosphorylation after being stimulated by these biological factors. As a negative gene regulating the PI3K signaling pathways, SHIP can induce the apoptosis of tumor cells by removing specifically PIP3, including PI (3, 4, 5) P3 and PI (1, 3, 4, 5) P4. Studies have found that the expression of the SHIP in the paracarcinoma tissue is obviously increased than that in primary tumors and metastatic lymph nodes, speculating that the SHIP, as a potential tumor suppressor genes, may adjust tumor invasion and metastasis through negative feedback effect in PI3K/Akt signal pathway.[40] PTEN and SHIP are regulators affecting phosphorylation of the signal path.[41] From this view, SHIP and PTEN play a similar role in breast cancer, but studies on the relationship between SHIP and lymphatic metastasis of breast cancer are a lack of exact data, whether loss expression or mutation of SHIP in breast cancer can promote lymphatic metastasis or not, it has yet to be further studied.


 > Conclusion Top


It is an indisputable fact that the loss expression or inactivation of tumor suppressor gene PTEN and SHIP is associated with the occurrence, development, and prognosis of breast cancer. However, the mechanism of its differential expression in breast cancer is still not clear, and it still needs more experimental and clinical researches to confirm which signal pathway specifically interfere with the development of breast cancer. We believe that with a comprehensive understanding of mechanisms and functions of PTEN, SHIP, it will definitely open a new chapter for the diagnosis, clinical treatment and prognosis judgment of breast cancer.

Financial support and sponsorship

The research project related with this thesis was subsidized by the National Nature Science Foundation (approve number: 81473687); The Natural Science Foundation of Shandong Province of China (ZR2009CM039, ZR2013HM038); Scientific research project in the Science and Technology Development Plan of Shandong province (2011HW084).

Conflicts of interest

There are no conflicts of interest.



 
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