| Breast cancer is one of most common causes of cancer deaths worldwide. Althoughsome pathological factors such as ER, PR and HER2have been wildly used for referencesin clinical diagnosis and treatment, their predictive ability of disease prognosis in breastcancer still have limitations. Therefore, it is necessary to identify reliable molecularprognostic markers in clinical practice for the treatment of breast cancer.The transcription factor Twist1belongs to the basic helix–loop–helix (bHLH)superfamily. It encodes a transcription factor that contains a basic helix-loop-helix(bHLH)domain and an amino-acid motif specific to proteins that are involved in the regulation oforganogenesis. Twist1was originally identified as one of the zygotic genes in Drosophilaresponsible for mesoderm development during embryonic morphogenesis. Consistent withits major role in organogenesis, under physiological circumstances, Twist1is primarilyexpressed in mesoderm-derived tissues. As a master regulator of embryonic morphogenesis,Twist1is also known to contribute to epithelialemesenchymal transition, invasion,metastasis, stemness, and chemotherapy resistance in cancer cells. Twist1is over-expressedin human breast cancers and usually associated with lymph-node and distant metastases andpoor prognosis, and thus is a potential target for breast cancer therapy.Part1SRC-1and Twist1are positively correlated and associated with poorprognosis in human breast cancerThe steroid receptor coactivator1(SRC-1, also known as NCOA1) is a member ofp160family, it has the ability to coactivate nuclear receptors such as ERα and PR in thepresence of hormones. Previous studies revealed that SRC-1plays a important role indevelopment and growth of reproductive organs and SRC-1also plays a critical role in cancer cell proliferation, invasion and metastasis through multiple pathways. Twist1hasbeen shown to induce EMT and plays a critical role in cancer cell metastasis. Althoug basicstudies have revealed that SRC-1serves as a coactivator for the transcription factor PEA3to enhance Twist1expression in breast cell lines, the correlation between SRC-1andTwist1in human breast cancer and their relationship with clinical parameters still remainunclear.In order to analyze the expression profiles of SRC-1and Twist1in human breastcancer and evaluate their possible prognostic values in breast cancer patients,immunohistochemistry was performed for detecting SRC-1and Twist1proteins on breastcancer with tissue microarray containing137specimens, in which123breast cancerpatients were followed up for a median of5years after surgery. Survival curves weregenerated using the Kaplan–Meier method. Multivariate analysis was performed by usingthe Cox proportional hazard regression model to assess the prognostic values of SRC-1andTwist1.Below we present the results of our study:1. There was an positive correlation between SRC-1and Twist1expression at proteinlevels (p=0.009).2. SRC-1-positive expression was correlated with HER2expression (P=0.024). Theprotein expression of Twist1was positively correlated with lymph node metastasis (p<0.001) and inversely associated with PR status(P=0.041).3. Patients with SRC-1or Twist1-positive expression had a poorer overall survival(OS) and disease-free survival (DFS) than those with SRC-1or Twist1-negative expression(p <0.05for all). In addition, SRC-1-negativeive/Twist1-negative patients had the best OSand DFS (p <0.01for both).4. In multivariate survival analysis, SRC-1expression, tumor stage and PR wereindependent prognostic factors related to OS (p=0.019,<0.001and0.020, respectively),Twist1expression, lymph node status and PR were found as independent predictors of DFS(p=0.006,0.001and0.029, respectively).Part2Studies on the distribution of Twist1protein in mouse organs and tissuesand the effects of inducible Twist1gene knockout on the physiological functions of miceBecause Twist1-null mice are embryonic lethal, the function of Twist1in adultanimals remains unknown. People with one Twist1germline mutant allele developSaethre-Chotzen syndrome. It is questionable whether Twist1can be targeted in cancerpatients without severe adverse effects.In this study, We found that Twist1is expressed in several tissues of mouse, includingfibroblasts of the mammary glands and dermal papilla cells of the hair follicles. We thendeveloped a tamoxifen-inducible Twist1knockout mouse model to knock out Twist1allelesin adult mice to define the effects of Twist1inactivation on the health of the adult animal.Our further studies were outlined as follows:1. Twist1knockout in6-week-old female mice did not affect mammary glandmorphogenesis and function during pregnancy and lactation.2. Although Twist1is not cyclically expressed in dermal papilla cells, knockout ofTwist1at postnatal day13(when hair follicles have developed) drastically shortened thetelogen phase and extended the anagen phase and thus accelerated hair growth.3. The Twist1null mice grew normally and were fertile. In both males and females,the knockout did not influence body weight gain, heart rate, or total lean and fatcomponents. The knockout also did not alter blood pressure in males, although it slightlyreduced blood pressure in females.In conclusion, we demonstrated for the first time that SRC-1and Twist1expressionsare positively correlated in human breast cancer. We also confirmed that SRC-1and Twist1expression are prognostic factors in human breast cancer. Moreover, combined expressionof SRC-1/Twist1could improve prognostic judgment for breast cancer patients.These results also indicate that Twist1is not essential for maintaining an overallhealthy condition in young and adult mice and that loss of function facilitates hair growth inadulthood, supporting Twist1gene or protein could be used as specific targets for breastcancer therapy without severe side effects. |
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