IRIC - Institute for Research in Immunology and Cancer

Published on December 7, 2022

Breast cancer is a heterogeneous disease, which cannot be effectively targeted by a common, single treatment. In two-thirds of cases, the estrogen receptor alpha (ERα), a receptor activated by sex hormones, is expressed and can be targeted therapeutically by hormone therapy. However, ERα levels can vary between and within tumors, complicating its detection and subsequent choice of therapy. The progesterone receptor (PR) is commonly used clinically as a co-marker for selection of tumors qualifying for hormone therapy. Indeed, this estrogen-regulated marker is thought to reflect ERa activity. In a new study published in the journal Cancers, Sylvie Mader, director of the Molecular Targeting in Breast Cancer Treatment Research Unit at IRIC, and her PhD student Lucas Porras show that PR detection imperfectly reflects ERα activity and identify a new, more reliable co-marker.

Clinical PR status does not accurately reflect ERα levels or activity

An analysis of all RNA present (transcriptome) in breast tumors revealed that in addition to variability in PR detection when its expression levels are low, PR may be absent in tumors expressing ERα and vice versa.

CAXII: a more reliable co-marker

The team subsequently performed an expression correlation analysis using the same breast cancer data. Among the group of genes whose expression correlated most strongly with that of the ERα gene, the scientists identified CAXII, which, like PR, is a target of estrogen signaling in breast tumors. This strong correlation was confirmed following analysis of two other databases of breast cancer samples. The team explains that this high degree of correlation at the RNA level stems from the regulation of CAXII by a cooperative action of ERα and GATA3, itself a regulator of ERα. Detection of CAXII in breast tumor collections using a specific antibody validated a superior performance in detecting ERα status compared to PR, whose clinical utility would be more associated with its prognostic value.

In conclusion, the work proposes the use of CAXII as a co-marker to confirm ERα status. Its localization to the cell surface, whereas ERα is found in the nucleus of cells, allows easy detection in co-labeling. It is also an asset to sort tumor cells according to their ERα expression level in heterogeneous breast tumors, which will facilitate the study of the causes of this heterogeneity and their consequences on the response to hormone therapies.

Cited study :

Porras Lucas, Gorse Faustine, Thiombane Ndeye Khady, Gaboury Louis, Mader Sylvie. CAXII Is a Surrogate Marker for Luminal Breast Tumors Regulated by ER and GATA3. Cancers. 2022; 14(21):5453.