TRPS1: a highly sensitive and specific marker for breast carcinoma, especially for triple-negative breast cancer

Abstract

Currently there is no highly specific and sensitive marker to identify breast cancer-the most common malignancy in women. Breast cancer can be categorized as estrogen receptor (ER)/progesterone receptor (PR)-positive luminal, human epidermal growth factor receptor 2 (HER2)-positive, or triple-negative breast cancer (TNBC) types based on the expression of ER, PR, and HER2. Although GATA3 is the most widely used tumor marker at present to determine the breast origin, which has been shown to be an excellent marker for ER-positive and low-grade breast cancer, but it does not work well for TNBC with sensitivity as low as <20% in metaplastic breast carcinoma. In the current study, through TCGA data mining we identified trichorhinophalangeal syndrome type 1 (TRPS1) as a specific gene for breast carcinoma across 31 solid tumor types. Moreover, high mRNA level of TRPS1 was found in all four subtypes of breast carcinoma including ER/PR-positive luminal A and B types, HER2-positive type, and basal-type/TNBC. We then analyzed TRPS1 expression in 479 cases of various types of breast cancer using immunochemistry staining, and found that TRPS1 and GATA3 had comparable positive expression in ER-positive (98% vs. 95%) and HER2-positive (87% vs. 88%) breast carcinomas. However, TRPS1 which was highly expressed in TNBC, was significantly higher than GATA3 expression in metaplastic (86% vs. 21%) and nonmetaplastic (86% vs. 51%) TNBC. In addition, TRPS1 expression was evaluated in 1234 cases of solid tumor from different organs. In contrast to the high expression of GATA3 in urothelial carcinoma, TRPS1 showed no or little expression in urothelial carcinomas or in other tumor types including lung adenocarcinoma, pancreatic adenocarcinoma, colon and gastric adenocarcinoma, renal cell carcinoma, melanoma, and ovarian carcinoma. These findings suggest that TRPS1 is a highly sensitive and specific marker for breast carcinoma and can be used as a great diagnostic tool, especially for TNBC.

Fig. 1. mRNA levels of TRPS1 and GATA3 in four subtypes of breast cancer and 30 other tumor types.

Breast carcinomas (BRCA) are in order as basal, HER2+, luminal B, and luminal A (red to dark green), and purple line is the top 80% expression in BRCA. Analyzed TCGA tumor types include ACC adrenocortical carcinoma, BLCA urothelial carcinoma, BRCA breast invasive carcinoma, CESC cervical squamous cell carcinoma and endocervical adenocarcinoma, CHOL cholangiocarcinoma, COAD colon adenocarcinoma, ESCA esophageal carcinoma, GBM glioblastoma, HNSC head-neck squamous cell carcinoma, KICH chromophobe renal cell carcinoma, KIRC clear cell renal cell carcinoma, KIRP renal papillary carcinoma, LGG low-grade glioma, LIHC hepatocellular carcinoma, LUAD lung adenocarcinoma, LUSC lung squamous cell carcinoma, MESO mesothelioma, OV ovarian serous cystadenocarcinoma, PAAD pancreatic adenocarcinoma, PCPG pheochromocytoma, PRAD prostate adenocarcinoma, READ rectal adenocarcinoma, SARC sarcoma, SKCM skin cutaneous melanoma, STAD stomach adenocarcinoma, TCGT testicular germ cell tumor, THCA thyroid carcinoma, THYM thymoma, UCEC uterine corpus endometrial carcinoma, UCS uterine carcinosarcoma, UVM uveal melanoma.

Fig. 2. TRPS1 and GATA3 expression in representative ER/PR+ breast cancer cases.

Case 1 shows a low-grade breast carcinoma with high expression of both TRPS1 and GATA3. Case 2 shows a high-grade breast carcinoma with high expression of TRPS1 and low expression of GATA3.

Fig. 3. TRPS1 and GATA3 expression in representative HER2+ breast cancer cases.

Case 1 shows an invasive ductal carcinoma with high expression of both TRPS1 and GATA3. Case 2 shows an invasive carcinoma with high expression of TRPS1 and negative GATA3.

Fig. 4. TRPS1 and GATA3 expression in representative nonmetaplastic TNBC cases.

Case 1 shows a poorly differentiated carcinoma with high expression of TRPS1 and intermediate to high expression of GATA3. Case 2 shows a poorly differentiated carcinoma with high expression of TRPS1 and negative GATA3.

Fig. 5. TRPS1 and GATA3 expression in representative metaplastic breast cancer cases.

Case 1 shows a metaplastic carcinoma of chondroid differentiation with high expression of TRPS1 and negative GATA3. Case 2 shows the giant/polymorphic nuclei of a metaplastic carcinoma with high expression of TRPS1 and negative GATA3. Case 3 shows a high-grade spindle/sarcomatous metaplastic carcinoma with high expression of TRPS1 and negative GATA3. Case 4 shows a metaplastic squamous cell carcinoma with high expression of TRPS1 and low expression GATA3.

Fig. 6. TRPS1 expression in other tumor types.

a Low expression in one urothelial carcinoma. b Low expression in one lung adenocarcinoma. c Intermediate expression in one ovarian serous carcinoma. d Intermediate expression in one salivary duct carcinoma. e Low expression in one pancreatic adenocarcinoma carcinoma. f Low expression in one melanoma.

Fig. 7. TRPS1 and GATA3 expression in benign breast ducts.

TRPS1 and GATA3 are expressed in the ductal epithelial cells of benign breast ducts.