|Year : 2015 | Volume
| Issue : 5 | Page : 11-15
Molecular markers' progress of breast cancer treatment efficacy
Dan Wang, Jingwei Xu, Guang Shi, Guanghao Yin
Department of Breast Surgery, The Second Hospital of Jilin University, Changchun City, Jilin Province 130041, China
|Date of Web Publication||31-Aug-2015|
Dr. Guanghao Yin
The Second Hospital of Jilin University, Changchun City, Jilin Province 130041
Source of Support: None, Conflict of Interest: None
Breast cancer is a famous malignant tumor which is caused by varieties of mutation in multiple genes. In order to detect breast cancer in an earlier time and take appropriate treatment which includes predicting treatment efficacy, we need a more accurate method of discovering the occurrence of breast cancer. With the development of molecular biology and biological detection technologies continue to emerge, molecular markers of breast cancer have gaining more and more widespread attention, and combining with molecular markers of breast cancer in clinical characteristic of individual treatment for breast cancer has become possible. In this paper, we will focus on the advances about molecular markers associated with treatment efficacy in recent years.
Keywords: Breast cancer, molecular marker, treatment efficacy
|How to cite this article:|
Wang D, Xu J, Shi G, Yin G. Molecular markers' progress of breast cancer treatment efficacy. J Can Res Ther 2015;11, Suppl S1:11-5
| > Introduction|| |
An increasing number of experimental trends for breast cancer research is also changing from molecular aspects of clinical features due to the high incidence of breast cancer in recent years.  Although the clinical research has made great progress, the local recurrence and distant metastasis rate is still at a very high level. Potential molecular markers have a major role in forecast treatment efficacy of breast cancer, observation on the prognosis, and identification of risk for treatment. Many molecular markers associated with breast cancer has been detected, such as estrogen receptor (ER),  human epidermal growth factor 2 (HER-2),  p53, and so on. Furthermore, recently studies show that noncoding RNA is closely related to the occurrence and development of breast cancer. Sakurai et al. indicated that when analyzing miRNAs in breast cancer as a biomarker, they should be examined as a cluster through miRNA profiling, rather than relying on the analysis of a single miRNA.  This paper reviewed the research progress of several breast cancer molecular markers which were associated with treatment effect.
| > Molecular Markers of Breast Cancer Cell Growth|| |
Tumor cells acquired the ability of growth and reproduce became a prerequisite for cancer, and breast cancer treatment is designed to inhibit the growth of cancer cells or clear the body's cells. The proliferation of tumor cells in breast cancer has been widely used to study the potential of growth, development, and metastasis of tumors.
Ki67 is a monoclonal antibody which can react with proliferative cell nuclear protein. Cell-cycle analysis showed that Ki67 antigen is present in the nucleus of the stages of mitosis, but static cell or G0 cells do not express this antigen. The level of Ki67 expression has been proposed to be a measure for quantification of cell proliferation in breast cancer samples.  High level of Ki67 correlates with ER negativity, HER-2 overexpression, and high-grade disease as well. Due to its character of presenting in hyperplastic normal cells, or tumor cells specifically, we consider Ki67 as a marker for evaluating the growth of special cell populations. However, some studies show that Ki67 provides some treatment value and could be used to identify such patients who need adjuvant chemotherapy. New foundation showed that Ki67 index was a surrogate marker to predict the treatment response of neoadjuvant chemotherapy.  A retrospective analysis of patients with breast cancer who was treated with optimal endocrine therapy showed that the difference in 4-year disease-free survival (DFS) was only 3% between the subpopulation of patients with high Ki67 and low Ki67 expression.  Kim et al. collected 9321 of hormone receptor-positive invasive cancer patients and assayed Ki67 level immunohistochemically.  The result shows that Ki67 level was higher in younger patients and very young patients had a poorer prognosis regardless of the Ki67 level. Furthermore, researchers found that Ki67 could predict efficacy of adjuvant chemotherapy. Previous studies has reported a statistically significant quantitative interaction between Ki67 expression and efficacy of adjuvant chemotherapy.  mTOR/S6K pathway could regulate cell growth, differentiation and proliferation, and protein synthesis process. The mechanism of Ki67 as a molecular marker of breast cancer was realized by mTOR/S6K pathway but not by MAPK pathway.  Therefore, Ki67 is involved in regulating the process of breast cancer cell growth and may be used as molecular markers of breast cancer treatment.
Topo II is an important enzyme in organism which was involved in DNA replication, transcription and regulation of nucleic acid, controlling the physiological functions of nucleic acids. Studies have shown that Topo II can be used as a molecular marker for breast cancer because anthracycline drugs could stabilize the crack complexes formatted by Topo II and DNA, then prevent Topo II fracture-induced by ligation and DNA double-strand DNA breaks, thus inhibiting cell proliferation.  Furthermore, assessed Topo II copy number in 670 cases of breast cancer show that changer of Topo II copy number is probably of limited value as a prognostic marker.  Accumulating evidences suggest that tumors are driven by a small population of cancer stem cells (CSCs) which may be resistant to current therapeutic approaches. Newly evidences showed that Topo II activity was increased in breast cancer cell CSCs and leaded to the increased sensitivity of breast cancer to Topo II inhibitor..  Topo II is a valuable prognostic indicator which may be one of the factors affecting the prognosis of patients with breast cancer.
| > Cell Cycle Proteins|| |
The changes of cell cycle will eventually lead to the formation of irregular survival because cell growth and changes in cell cycle are the basis of tumor formation. Cancer cells bypass normal controls over mitotic cell-cycle progression to achieve a deregulated state of proliferation. Moreover, cell cycle may directly result in breast cancer treatment response through observing the changes in cell cycle. Cyclin D1 is an important molecular driver of human breast cancer. A study that included 50 patients with primary invasive breast cancer showed that cyclin D1 expressed in 30 tumor pairs among them, and cyclin D1 expression in terms of nuclear intensity was significantly decreased (P = 0.008) after statin treatment in paired tumor samples.  Moreover, high cyclin D1 expression defines a subgroup of luminal-like breast cancer patients with a high risk of relapse and death.  However, estrogen and ER pathway play a role in the regulation of cell-cycle protein cyclin E expression followed by the cell-cycle changes in breast cancer.  Moreover, recent research discovered that cyclin A and cyclin E were involved in the carcinogenesis of endometrium in women with breast cancer and under tamoxifen treatment. Follow-up of the patients using these 2 markers is highly recommended starting from the 12 th month.  Therefore, cell-cycle proteins may be used as alternate molecular markers of breast cancer treatment. 
| > Other Cell Growth Molecular Markers|| |
Proliferating cell nuclear antigen (PCNA) is a nucleus DNA polymerase δ auxiliary protein which was directly involved in DNA synthesis, protein expression, and cell proliferation. PCNA level in stationary cells was very low, and PCNA is a positive factor in the regulation of growth and PCNA index is evaluated more objective and accurate index of cell proliferation. When PCNA was in high level, the time of active cell proliferation and doubling became short, and patients with DFS and overall survival rates of low levels of tumor cell differentiation, high malignancy and tissue invasion were in low level.  Hyaluronan-binding protein 1 (HABP-1) is a protein with high affinity for HA. High HABP-1 expression is correlated with poor overall survival in breast cancer patients and is a significant independent prognostic biomarker because HABP-1 regulates proliferation and migration of breast cancer cells.  As we know, noncoding RNAs mostly were involved in tumor formation and development. Many studies have found that miRNA can be predicted as a potential molecular marker of breast cancer treatment, such as miR-24-3p,  miR-21,  miR-365,  and so on. Although we have found that these can be used as a predictive clinical marker on molecular markers of breast cancer treatment, but these markers predicting the treatment efficacy still put at the phase of cell growth segment.
| > Hormone-Related Molecular Markers|| |
Molecular markers of breast cancer associated with the hormone are mainly occurred in the clinical treatment of the body and hormone-related changes. These molecules play a critical role in predicting cancer prognosis and treatment effects.
Previous studies submitted that ER-negative breast cancer patients showed overall low degree of histological differentiation, and ER-negative tumors and cell lines in vitro were more sensitive to chemotherapy.  However, the current understanding of the mechanism of estrogen-induced apoptosis is described as a consequence of acquired resistance to long-term antihormone therapy in ER-positive breast cancer. The ER signal transduction pathway remains a target for therapy in breast cancer despite "antiestrogen" resistance, but becomes a regulator of resistance.  Due to the clinical performance and biological characteristics, treatment and prognosis in ER-positive breast cancer are different with that of ER-negative breast cancer, and we often fall into four categories of breast cancer in order to facilitate treatment, including patients who showed ER and HER-2 positive, or ER, PR and HER-2 both showed negative. Based on ER involved in proliferation and apoptosis of breast cancer cells, estetrol (E4) presents an antitumor activity by decreasing the strong proliferative effect of estradiol (E2), and ER alpha is the predominant receptor mediating its effects.  Progesterone receptor (PgR) absence was found to be a negative prognostic factor in breast cancer patients with ER-positive locoregional recurrence, and PgR status could be a biological marker in ER-positive recurrent breast cancer. 
PR is the end product of estrogen, and its main function is to cause and enhance estrogen response to ER and lead to the catalytic and synergistic effects. PR was based on expression of ER, and PR expression in breast cancer tissue but not ER may less than 1%.  PR status exerts a significant impact on the prognosis of ER+/HER-2-breast cancer based on the foundation of 400 patients with ER-positive and HER-2-negative tumors.  PR can be divided into the PR-A and PR-B subtypes. The two PgRs are co-expressed at equivalent levels in normal breast, but early in carcinogenesis normal levels of PR-A and PR-B are frequently disrupted. Studies discovered that imbalanced PR-A and PR-B expression in breast tumors may contribute to disease outcome and relative benefit from endocrine treatment.  New mechanism discovered that the deregulation of PR may result in breast cancer cell de-differentiation owning to loss of miR-141 triggered by progesterone.  PR and its target genes play an important role in progestin-induced activation by cyclin A2 and its associated kinase activity in breast cancer cells.  However, in clinical practice, ER and PR together are often used as predictors and prognostic factors. ER and PR were kind of significant factors in molecular markers of breast cancer. Breast is target organs of sexhormone and two types of estrogen and PgRs are existed under normal circumstances. Estrogen and progestin receptors may partially or fully lost when breast epithelial change into cancerous. If breast tumors can still be detected in these two types of receptors, indicating that the cancer endocrine, hormone therapy and therapeutic effect and prognosis are generally well[AQ: clarity]. According to the above phenomena, we regularly take ER and PR expression as a leading indicator of breast cancer treatment options internationally and included a breast cancer recurrence risk assessment parameter.
Other types of molecular markers of breast cancer
HER-2 is an oncogene and activated by the formatted of dimer. Early response genes such as c-jun and c-fos in the nuclear transcription levels increased, then a series of changes happened in mitosis, and caused cell proliferation, differentiation, and migration when HER-2 gene was activated, and eventually induced tumor formation. Several studies showed that HER-2 was positively correlated with histological grade in breast cancer, the prognosis is worse when the expression rates higher. , In a study of patients with breast cancer, oncogene amplification of HER-2 were reported for the first time and noted that HER-2 copied properties can lead to tumor recurrence, and poorer clinical outcomes are adverse factors on prognosis in patients with operable breast cancer.  HER-2 is an independent biological indicator of poor prognosis in breast cancer, which is worth more than hormone receptor and tumor volume, and it is second only to the lymph node status in breast cancer prognostic indicator. HER-2-positive breast cancer in combination with chemotherapy in patients with anthracycline-containing program should be selected, and several studies have shown that a nonanthracycline containing anthracycline chemotherapy can significantly improve quality of life.  HER-2 overexpression in primary tumors might be a predictive marker for good efficacy of anthracycline-based neoadjuvant chemotherapy.  And breast cancer with HER-2-negative could significantly benefit from neo-adjuvant chemotherapy better than HER-2-positive patients.  Although chemotherapy followed anti-HER-2 therapy may bring more adverse reactions, the efficient and progression-free survival of HER-2 target therapy or combined with endocrine were better than chemotherapy treatment alone.
Current discovery related molecular markers of breast cancer and breast cancer treatment including gene. Oncogenes can be divided into oncogene and tumor suppressor genes, and their activation or inhibition are bound up with carcinogenesis. p53 is by far the most relevant tumor suppressor gene, also known as the star molecule. Patients with p53-positive biopsy specimens develop into invasive cancer risk increased compared with p53-negative patients.  A study demonstrated that p53 accumulation is a strong predictor of both early and late recurrence in ER-positive breast cancer patients treated with aromatase inhibitors as adjuvant endocrine therapy and p53 gene alteration might be a key biological characteristic of ER-positive breast cancer.  In ER(+) p53 WT breast cancers, ER-induced inhibition of p53 apoptotic response would lead preferentially to tumor cell senescence and subsequent resistance to treatment, and conversely, in ER-negative p53 mutated breast cancers, accumulation of genetic abnormalities would lead to mitotic catastrophe and subsequent better response. 
Tumor multidrug resistance (MDR)-related gene changes will have an impact on breast cancer treatment. MDR severely blocks the successful management of breast cancer. Overexpression of MDR1 accounts for the major factor in the development of MDR in breast cancer. A finding implied that autophagy might be a target to overcome MDR in breast cancer cells, and clinical use autophagy inhibitors might be one of the important strategies for overcoming MDR in breast cancer therapy.  The product of MDR1, P-glycoprotein, is an adenosine triphosphate-dependent efflux pump associated with chemotherapy failure in breast cancer. The present study showed a pathway in which paclitaxel induced MDR1 expression, possibly illuminating a potential target pathway for the prevention of MDR1-mediated drug resistance which was based on Erk1/2-induced Egr-1 accumulation promoted MDR1 transcription, thereby induced drug resistance observed in paclitaxel-resistant MCF-7 cells.  A biological target for therapy of MDR1 MDR in breast cancer study found that derivatization by benzo-annulation of tryptanthrin ameliorated the MDR-reversing effect of tryptanthrin and may pave the way to the discovery of a novel potent adjuvant agent for chemotherapy.  Due to the emergence of drug resistance in the treatment of breast cancer showed an enormous impact on therapeutic effect, the current studies on the molecular markers of drug resistance still seems to be very important.
| > Perspective|| |
These molecular markers are now have been used in neoadjuvant chemotherapy, later rescued and postoperative adjuvant therapy in the treatment of predicted breast cancer treatment. For clinical, the use of these molecular markers showed proper selection of individualized treatment which may provide a strong protection. In addition, a number of new molecular markers were discovered in recent years that require a number of clinical evidence to support their application. Therefore, we need the unremitting efforts to explore the evidence, and we believe that the value of molecular markers in clinical diagnosis and therapeutic will be higher in the future treatments of breast cancer.
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Conflicts of interest
There are no conflicts of interest.
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