Cystatin M loss is associated with the losses of estrogen receptor, progesterone receptor, and HER4 in invasive breast cancer

다국어 초록 (Multilingual Abstract)

<P><B>Introduction</B></P><P>This study was aimed at understanding the clinicopathological significance of cystatin M loss, and investigating possible factors responsible for cystatin M loss in breast cancer.</P><P><B>Methods</B></P><P>The expression of estrogen receptor (ER), progesterone receptor (PR), HER2, HER4, and cystatin M was retrospectively analyzed using immunohistochemistry in 117 patients with ductal carcinoma <I>in situ </I>(DCIS) and in 175 patients with invasive breast cancer (IBC). The methylation status of <I>CST6 </I>gene encoding cystatin M was evaluated using methylation-specific polymerase chain reaction (PCR) in formalin-fixed paraffin-embedded tissues from 292 participants and using pyrosequencing in fresh-frozen tumor and matched normal tissues from 51 IBC patients.</P><P><B>Results</B></P><P>Cystatin M loss was found in 9 (8%) of 117 patients with DCIS and in 99 (57%) of 175 with invasive breast cancer (IBC) (<I>P </I>< 0.0001). Cystatin M loss was found in 58 (57%) of 101 HER2-negative IBCs and in 41 (55%) of 74 HER2-positive IBCs, and this difference was not statistically significant (<I>P </I>= 0.97). However, cystatin M loss was significantly associated with the loss of ER (<I>P </I>= 0.01), PR (<I>P </I>= 0.002), and HER4 (<I>P </I>= 0.003) in IBCs. Cystatin M loss occurred in 34 (76%) of the 45 HER4-negative IBCs and in 65 (50%) of the 130 HER4-positive IBCs. Multivariate analysis showed that cystatin M loss occurred at a 3.57 times (95% CI = 1.28 to 9.98; <I>P </I>= 0.01) higher prevalence in the triple-negative IBCs of ER, PR, and HER4 than in other subtypes, after adjusting for age. The quantity of <I>CST6 </I>methylation was associated with ER loss (<I>P </I>= 0.0002) in IBCs but not with the loss of PR (<I>P </I>= 0.64) or HER4 (<I>P </I>= 0.87).</P><P><B>Conclusions</B></P><P>The present study suggests that cystatin M loss may be associated with the losses of ER, PR, and HER4 in IBC.</P>