| Background:Breast cancer and thyroid cancer are two kinds of malignant tumors with high incidence in women.In recent years,many studies attempted to reveal the internal relationship between breast cancer and thyroid cancer.When a patient with a malignant tumor suffers from a second tumor which is not directly formed by the recurrence and metastasis of the first tumor,the second tumor is defined as the second primary tumor.There is evidence that female breast cancer patients are more likely to develop secondary primary thyroid cancer than ordinary women.At the same time,women with thyroid cancer also have a higher risk of developing secondary primary breast cancer.These findings suggest that there seems to be a mutually reinforcing relationship between breast cancer and thyroid cancer in terms of incidence.Some studies have pointed out that breast cancer patients with second primary thyroid cancer have a lower risk of recurrence and death than patients with simple breast cancer.This means that thyroid cancer also affects the prognosis of patients with breast cancer.In order to explore the relationship between these two kinds of female malignant tumors,this study evaluated the clinical characteristics of female patients with primary thyroid cancer and breast cancer successively,and determined the effect of the sequence of these two kinds of malignant tumors on the survival of the patients.and to explore whether this effect is related to the effect of thyroid hormone on breast cancer cells.Methods:1.We selected female cancer patient data from the Surveillance,Epidemiology and final outcome(SEER)database.Female patients with breast or thyroid cancer from 2010 to 2018 were selected and divided into four groups.The first group was a simple breast cancer group(BC group),which had 267284 patients.The second group was a simple thyroid cancer group(TC group),which had 71102 patients.The third group contained the female patients who were diagnosed with thyroid cancer and then developed breast cancer(TC2BC group).The fourth group contained the female patients who were diagnosed with breast cancer and then developed thyroid cancer(BC2TC group).We recorded and analyzed the following clinical information: age,race,size of breast tumor,status of lymph node involvement,histological type of breast tumor,grade of breast tumor,TNM stage of breast tumor,distant metastasis of breast cancer,expression of estrogen receptor(ER)in breast tumor,expression of progesterone receptor(PR)in breast tumor,Expression of human epidermal growth factor receptor(Her-2)in breast tumors,molecular subtypes of breast tumors,history of breast cancer surgery,survival time of patients and causes of death.Chi-square test was used to analyze the differences in clinical characteristics between groups.Univariate and multivariate Cox regression analysis was used to determine the risk factors associated with overall survival(OS)and disease-specific survival(DSS).To balance the baseline data of patients in the BC group and the BC2 TC group,we used a 1:1 propensity score match.Kaplan-Meier log-rank test was used to analyze the survival among groups and subgroups.2.First of all,the GEO database was used to analyze the differential gene analysis and GO pathway enrichment analysis of ER positive human breast cancer transplantation model treated with estrogen and thyroid hormone.Secondly,two estrogen-dependent breast cancer cell lines MCF-7 and T-47 D and a triple negative breast cancer cell line MDA-MB-231 were selected.The rats were divided into four groups: the first group was blank control,the second group was added estradiol(E2)10n M,the third group was added thyroid hormone T3 25 n M + thyroid hormone T4100 n M,and the fourth group was added estradiol 10 n M + thyroid hormone T3 25 n M+ thyroid hormone T4 100 n M.After treatment,CCK8 cell proliferation assay was used to detect cell proliferation;wound healing assay was used to detect cell migration;Transwell cell invasion assay was used to detect cell invasion;and flow cytometry was used to detect cell apoptosis.Finally,Western Blot assay was used to detect the expression of ERK1/2,p-ERK1/2,ERα,p-S118-ERα,Cyclin A,Cyclin B,Cyclin D1 and Cyclin E in MCF-7 cells.One-way ANOVA univariate analysis of variance was used to analyze the differences among different treatment groups.Results:1.There were significant differences among BC group,TC2 BC group and BC2 TC group in the following clinical characteristics: age,race,size of breast tumor,status of lymph node involvement,breast tumor grade,TNM stage and molecular subtype of breast tumor.Univariate and multivariate Cox regression analysis showed that the second primary thyroid cancer was a protective factor for OS(HR: 0.531(0.391-0.722)p<0.001)and DSS(HR:0.500(0.340-0.735)p=0.004)in patients with breast cancer.In addition.The following clinical features are independent influencing factors of OS and DSS in patients with breast cancer: age,race,size of breast tumor,number of lymph nodes involved,grade of breast tumor,histological type of breast tumor,TNM stage of breast tumor,distant metastasis of breast cancer,history of breast cancer operation,expression of ER in breast tumor,expression of PR in breast tumor,Expression of Her-2 in breast tumors and molecular subtypes of breast tumors.After propensity score matching,719 pairs of breast cancer patients with or without second primary thyroid cancer were included in the survival analysis.The results showed that when the baseline data were flat,OS(HR:0.325(0.232-0.455)p<0.001)and DSS(HR:0.272(0.184-0.404)p<0.001)in BC2 TC group were still better than those in BC group.Subgroup survival analysis showed that the OS of patients in BC2 TC group was better than that in BC group in many subgroups(p<0.05).Except for the age ≤ 40 subgroup(HR: 0.278(0.052-1.476)p=0.073),Asian subgroup(HR:0.590(0.273-1.276)p=0.237),breast tumor size < 50 mm subgroup(HR: 0.482(0.228-1.021)p=0.056),the number of involved lymph nodes was 0 subgroup(HR:0.638(0.327-1.245)p=0.160),The number of positive lymph nodes ≥ 10(HR: 0.625(0.217-1.802)p=0.448),lobular carcinoma subgroup(HR: 0.895(0.297-2.697)p=0.848)and triple negative breast cancer subgroup(HR: 0.953(0.581-1.331)p=0.210).The DSS of BC2 TC group was better than that of BC group in many subgroups(p<0.05).Except for the age ≤ 40 subgroup(HR: 0.278(0.052-1.476)p=0.073),Asian subgroup(HR: 0.768(0.302-1.956)p=0.602),breast tumor size >50mm subgroup(HR: 0.462(0.199-1.071)p=0.096),the number of positive lymph nodes was 0 subgroup(HR: 0.523(0.217-1.262)p=0.121),The number of involved lymph nodes ≥ 10(HR: 0.442(0.145-1.350),p=0.262),lobular carcinoma subgroup(HR: 0.749(0.229-2.448)p=0.655),Her-2 overexpressed breast cancer subgroup(HR:0.396(0.155-1.011)p=0.052)and triple negative breast cancer subgroup(HR: 0.894(0.692-1.107)p=0.285).2.Bioinformatics analysis showed that compared with ER-positive human breast cancer treated with estrogen only,the up-regulated genes in ER-positive breast cancer treated with thyroid hormone + estrogen were mainly distributed in cell movement,growth and the opening of various ion channels.For ER positive breast cancer cells MCF-7 and T-47 D,estradiol and thyroid hormone T3+T4 promoted the proliferation,invasion and migration of these two kinds of cells.Estradiol promoted these two kinds of cells more than thyroid hormone,and there was a synergistic effect on the promotion of MCF-7 and T-47 D when the two hormones existed at the same time.For ER-negative breast cancer cell line MDA-MB-231,estradiol and thyroid hormone had no significant effect on its proliferation,invasion and migration.In addition,estradiol and thyroid hormone T3+T4 could reduce the apoptosis of ER-positive breast cancer cells MCF-7 and T-47 D,but had no significant effect on the apoptosis of ER-negative breast cancer cell line MDA-MB-231.The results of Western Blot assay showed that estradiol upregulated the expression of p-ERK1/2,p-S118-ERα,Cyclin A,Cyclin B,Cyclin D1 and Cyclin E protein compared with the control group.The trend of thyroid hormone group was consistent with that of estrogen group.In addition,compared with the estrogen group,the expression of these proteins was higher in the thyroid hormone + estrogen group.Conclusions:1.Second primary thyroid cancer can improve the prognosis of breast cancer patients,especially for Luminal female breast cancer patients.Whether they had thyroid cancer before suffering from breast cancer had no significant effect on the prognosis of patients with breast cancer.2.Both estradiol and thyroid hormone can promote the proliferation,migration and invasion of two kinds of luminous breast cancer cells MCF-7 and T-47 D,and the promoting effect of estradiol on them is more significant than that of thyroid hormone.The co-existence of estradiol and thyroid hormone had a synergistic effect on the promotion of MCF-7 and T-47 D cells.However,estradiol and thyroid hormone had no significant effect on the proliferation,migration and invasion of MDA-MB-231 breast cancer cells.In ER positive breast cancer cell MCF-7,both estradiol and thyroid hormone can activate ERK1/2 to induce the phosphorylation of ERα at serine118,thus promoting the growth and proliferation of breast cancer cells.And when the two hormones exist at the same time,the promoting effect is more significant. |
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