Prognostic significance of tumor-related proteases as a function of the estrogen receptor status

Abstract

IntroductionEstrogen receptor (ER) determination is a standard tool used to evaluate the prognosis of breast cancer (BC) and progesterone receptor (PgR) expression, which is determined at the same time, can reflect ER functionality.1 However, simply ascertaining the ER and PgR status might be insufficient to accurately appraise the prognosis of patients or their ability to respond to treatment. 2Some other indicators recently recognized as prognostic factors 3 will probably be included in the near future as routine parameters for personalized therapeutics. In particular, those proteins that reflect the functional integrity of the estrogen response pathway could be useful.Proteases and their inhibitors have been a subject of interest in BC since they were demonstrated to play a role in invasiveness, tumor spread and metastatic processes. [4][5][6][7] Particularly during the last years, two serine proteases, urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1), were recognized, with level of evidence I (LOE I), as biomarkers of the prognosis, in the recent panel expert consensus.3 These proteases are involved in collagenase IV destruction and the degradation of the basement membrane and therefore promote the metastatic process. 8,9Background: Tumor-related proteases such as urokinase-type plasminogen (upa), plasminogen activator inhibitor (paI-1) and cathepsin D (cath-D) are involved in the prognosis of breast cancer (BC) and promote the metastatic process. We investigated the relationship between these proteases and their prognostic significance according to the eR status.Results: Quantitative levels of upa and paI-1 were higher in eR -patients (p < 0.001) whereas no difference was observed for cath-D levels in eR subsets (p = 0.96). In patients with a positive and highly positive eR status, a high cath-D level was associated with a poorer prognosis. patients in the highly positive eR group experienced poorer survival in the group with a high paI-1 level compared to the group with a low paI-1 level. In eR + patients, cath-D (p = 0.02) and the tumor size (p = 0.03) were independent factors for Os.Methods: upa, paI-1 and cath-D levels were prospectively measured in tumor from 316 patients with primary BC. The distribution and relationship between these proteases and eR subsets were analyzed as well as the prognostic significance.Conclusion: The prognostic significance of proteases is modulated by the eR status. Cath-D and paI-1 could identify a high-risk group with an adverse outcome in eR + patients.

Relationships of protein biomarkers of the urokinase plasminogen activator system with expression of their cognate genes in primary breast carcinomas

“…Results revealed that an increase of uPA, uPAR, or PAI‐1 protein content was not correlated with patient age. Relationships between other biomarkers for breast cancer (eg, ER or PR protein) in intact tissue biopsies and patient age have exhibited associations for breast cancer patients, though the literature is conflicting . Similarly, our findings established relationships between biomarker protein content of the uPA system and either ER or PR status of the primary carcinoma.…”

Nuclear cathepsin D enhances TRPS1 transcriptional repressor function to regulate cell cycle progression and transformation in human breast cancer cells

“…Many reports indicated that Cath-D is mitogenic in BCC [ 5 – 8 , 10 – 12 ]. More recently, high Cath-D levels were associated with poor prognosis in patients with ER + breast cancer [ 51 , 52 ]. Moreover, TRPS1 is overexpressed in breast cancer [ 23 ] and its expression is linked to the ER + , GATA3 and HER2 status [ 53 – 55 ] and to the EMT-negative phenotype, as shown here for TRPS1 and Cath-D [ 24 ].…”

A prognostic model to predict outcome of patients failing to achieve pathological complete response after anthracycline‐containing neoadjuvant chemotherapy for breast cancer

“…Some investigators suggest that Cathepsin D plays an important role in regulating the effect of oestrogen on tumour growth. Thus, an increased level of Cath‐D is considered to be associated with worse DFS and OS in early breast cancer patients, especially in patients with ER+ 24, 25. However, printed data about Cath‐D expression and its relationship with prognosis after NCT is limited because it is not a routinely used marker in clinical practice.…”