It is well established that only estrogen receptor (ER)-positive tumors benefit from hormonal therapies. We hypothesized that a subgroup of breast cancer patients expresses estrogen receptor a (ERa), but fails to respond to hormonal therapy due to the expression of a non-functional receptor. We analyzed a series of 2,658 ERa-positive HER2-negative breast tumors for ERa and progesterone receptor (PR) status as determined by mRNA expression and for their molecular subtypes (Luminal type vs Basal type, assessed by BluePrint molecular subtyping assay). In addition, we assessed the recurrence risk (low vs high) using the 70-gene MammaPrint signature. We found that 55 out of 2,658 (2.1 %) tumors that are ERa positive by mRNA analysis also demonstrate a Basal molecular subtype, indicating that they lack expression of estrogenresponsive genes. These ERa-positive Basal-type tumors express significantly lower levels of both ERa and PR mRNA as compared to Luminal-type tumors (P.0001) and almost invariably (94.5 %) have a high-risk MammaPrint profile. Twelve of the MammaPrint genes are directly ERa responsive, indicating that MammaPrint assesses ERa function in breast cancer without considering ERa mRNA levels. We find a relatively high expression of the dominant negative ERa splice variant ERD7 in ERapositive Basal-type tumors as compared to ERa-positive Luminal-type tumors (P.0001). Expression of the dominant negative ERa variant ERD7 provides a rationale as to why tumors are of the Basal molecular subtype while staining ERa positive by immunohistochemistry. These tumors may lack a functional response to estrogen and consequently may not respond to hormonal therapy. Our data indicate that such patients are of MammaPrint high recurrence risk and might benefit from adjuvant chemotherapy. See article.
Publication Name: Breast Cancer Research and Treatment