| PURPOSE:It has been found that skewed X chromosomal inactivation (SXCI) in blood cells was a rare event in neonates and young healthy women, but relatively frequent in aged females, and was associated to an increased risk for pulmonary and esophageal carcinomas. In this survey, we intended to determine the relationship between SXCI and breast cancer development. Meanwhile, androgen receptor (AR) expression was also demonstrated in breast carcinoma tissue.METHOD:Genomic DNA was extracted from peripheral blood neutrophil cells from 206 females who were suspected as breast tumors. Exon 1 of AR gene was amplified, with its products from different alleles resolved on denaturing polyacrylamide gels and visualized by ethedium bromide. Corrected ratio (CR)≥3 and CR≥10 were used as the criteria of SXCI separately. SXCI frequencies of patients of different age groups were compared with those of the corresponding healthy women. Meanwhile, tissue arrays were prepared and immunohistochemical reactions were performed for AR molecules. Immuno-reactivity of AR in infiltrating ductal carcinoma (IDC) and ductal carcinoma in situ (DCIS) was assessed semiquantitatively, the expression levels were analyzed with several clinicopathological parameters. Immunohistochemical reactions were also performed for CK5/6, CK14, EGFR and E-cadherin to describe the features of triple negative breast carcinoma (TNBC).RESULT:Of the 154 informative samples from patients with breast carcinoma,52 (34%) showed a CR up to 3, and 23 (15%) showed a CR up to 10. Of the 310 samples from healthy women of comparable ages,50 (16%) showed a CR up to 3, and 18 (6%) showed a CR up to 10. SXCI, either defined as CR≥3 or CR≥10, were more frequent in patients than in healthy individuals (P= 0.000; P= 0.002). Of the 33 samples from younger patients (≤40 years),12 (36%) showed a CR up to 3, and 5 (15%) showed a CR up to 10. Of the 120 samples from healthy women of comparable ages,7 (6%) showed a CR up to 3, and 1 (1%) showed a CR up to 10. SXCI, either defined as CR≥3 or CR≥10, were more frequent in young patients than in corresponding healthy individuals (P= 0.000; P= 0.002). The difference of SXCI frequencies in patients older than 40 years and corresponding healthy individuals was relatively smaller. Of the 121 samples from older (> 40 years) patients,40 (33%) showed a CR up to 3. Of the 190 sample from corresponding healthy individuals,43 (23%) showed a CR up to 3. The frequencies of these two groups were significantly different (P=0.043). Of the 121 samples from older (> 40 years) patients,18 (15%) showed a CR up to 10. Of the 190 sample from corresponding healthy individuals,17 (9%) showed a CR up to 10, The frequencies of these two groups were not different (P= 0.107).Positive expression of AR was observed in 109 (70%) of the 156 IDC samples. Its level was found to be associated with ER (P=0.001) and progesterone receptor (PR) (P = 0.000) expression. Loss of AR expression was observed preferentially in samples from younger patients (≤40 years) (P= 0.038), and was associated to high grade histology of the tumors. No significant relationships were observed between AR expression and tumor size, node metastasis, the high level of HER2 expression (P> 0.05). Of the 45 samples from DCIS patients,38 (84%) were AR positive. No significant relationship was observed between its expression and histological grades. Of the 24 IDC samples with DCIS component,22 (92%) showed consistent reaction in infiltrating parts and in situ parts.The positivity rate of AR was lower in TNBC (29%,4/14) than in non-TNBC (74%, 105/142) (P= 0.001) samples. No significant differences were observed in the expression of E-cadherin, CK5/6, CK14 and EGFR in TNBC and non TNBC samples (P> 0.05).When defined as CR≥3, SXCI frequency in AR negative younger (≤40 years) patients (62%,8/13) was higher than in AR positive younger (≤40 years) patients (23%, 3/13) (P= 0.047).CONCLUSION:SXCI in peripheral blood neutrophil cells was more frequent in breast cancer patients compared to healthy women. This was prominent in younger (≤40 years) patients compared to corresponding healthy women. It seems conceivable that SXCI confer increased risk for breast carcinoma, particularly in young women.In IDC samples, AR positivity was associated with those of ER and PR. Loss of AR expression was associated to an early onset of the tumor (≤40 years), high grade histology and occurrence of TNBC. Loss of AR expression may play some role in the development of breast carcinoma especially in young patients. Contrast to IDC, DCIS samples did not show an association between AR expression and histological grades. For the DCIS component, AR immunoreactivity was consistent with the IDC component in samples of IDC accompanied with DCIS.SXCI in blood cells in young (≤40 years) breast cancer was associated with the loss of AR expression in tumor.
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