Stromal Immunoglobulin κC Expression Is Associated With Initiation Of Breast Cancer In TA2 Mice And Human Breast Cancer

The initiation of spontaneous breast cancer(SBC)in Tientsin Albino 2(TA2)mice is related to mouse mammary tumor virus(MMTV)infection,and MMTV amplification is hormonally regulated.To explore the insertion site of MMTVLTR in TA2 mouse genome,reverse PCR and nested PCR were used to amplify the unknown sequence on both sides of the MMTV-LTRSAG gene in SBC and normal breast tissue of TA2 mice.Furthermore,the clinicopathological significance of the insertion site was evaluated in 43 samples of normal breast tissue,46 samples of breast cystic hyperplasia,54 samples of ductal carcinoma in situ,142 samples of primary breast cancer,and 47 samples of lymph node metastatic breast cancer by RNA in situ hybridization.We confirmed that the insertion site of the MMTV-LTRSAG gene was located between Igκv2-112 and Igκv14-111 in chromosome 6 of TA2 mouse.IGκC was localized in the stromal cells of TA2 mouse with SBC and in human breast cancer tissues.Tumor cells were negative for IGκC in RNA in situ hybridization.The positive staining index of IGκC in stromal cells was the highest in lymph node metastatic breast cancer,followed by primary breast cancer,ductal carcinoma in situ,and breast cystic hyperplasia.Furthermore,the positive staining index of IGκC related with the expression of ER,PR,HER2,and Ki-67.Our findings showed that stromal IGκC expression was associated with the initiation of SBC in TA2 mice.IGκC may be a high-risk factor for the initiation and progression of human breast cancer.Breast cancer is a highly common type of cancer and a serious threat to women’s health.Surgery accompanied with chemotherapy and targeted therapy is the most successful treatment strategy for breast cancer.However,40% of the patients die due to recurrence and metastasis 1.The initiation of breast cancer is hormonally dependent.The mechanisms underlying hormone-regulated development of breast cancer are complicated and involve different pathways 2-5.It has been reported that the human genome carries a number of distinct endogenous retroviral sequences that exhibit sequence similarity with MMTV.Wang et al.reported that a 660-bp MMTV-like env gene sequence was found in approximately 38% of the sampled human breast cancer tissues,but not in normal breasttissues or other tumors.Tianjin Medical University established the spontaneous breast cancer(SBC)mouse model,TA2,after more than 50 years of research on this topic,and the incidence of SBCin this model is more than 80%.The incidence of SBC was dependent on gravidity and frequency of pregnancy,and mouse mammary tumor virus(MMTV)infection.MMTV is a retrovirus that is characterized by long terminal repeats(LTRs).MMTV LTR-likesequencescontain hormone-responsive elements(HREs),transcription enhancer factor-1(TEF-1)family elements,and an open reading frame(ORF)for superantigen(SAG)6.Expression of the SAG gene,which is present in the provirus,is responsible for the production of a SAG.The MMTV promoter contains an HRE that can bind with progestin,glucocorticoid receptors,and androgen receptors to promote the expression of MMTV genes 10.Our previous studies confirmed that combined exogenous estradiol and progesterone treatment induces the initiation of breast cancer in TA2 mice without ovaries.As a retrovirus,MMTV can integrate its genome into the mouse genome.When the virus DNA is inserted inside or even near an oncogene,it is able to change the expression of that gene,leading to development of cancer.MMTV remains dormant until stimulated by hormones.The hormones bind to the repeat sequence,TGTTCT,in the HRE of MMTV-LTR.The incidence of SBC in TA2 mice is related to gravidity and frequency of pregnancy and MMTV infection.Estradiol and progesterone can bind to the HRE and subsequently induce the initiation of breast cancer.The initiation of SBC in TA2 mice may be similar to the human pregnancy-associatedbreast cancer(PABC).PABC is defined as breast cancer diagnosed during pregnancy orwithin one year after delivery.Breast cancer has a high incidence the first year after pregnancy.The mechanism underlying the development of PABC involves the hormonal changes during adolescence and pregnancy.Furthermore,our previous studies have proved that SBC in TA2 mice is triple negative,which is an important subtype of invasive breast cancer with negative expression of the estrogen receptor(ER),progesterone receptor(PR),and HER2.Triple-negative breast cancer is more likely to affect younger women,and its prognosis is poor.