PUBLICATION:
Breast Cancer Res Treat (2013) 140:475โ€“484 DOI 10.1007/s10549-013-2648-1

AUTHORS:
Floris H. Groenendijk, Wilbert Zwart, Arno Floore, Stephanie Akbari, Rene Bernards

ABSTRACT:
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 ฮฑ (ERฮฑ), but fails to respond to hormonal therapy due to the expression of a non-functional receptor. We analyzed a series of 2,658 ERฮฑ-positive HER2-negative breast tumors for ERฮฑ and progesterone receptor (PR) status as determined by mRNA expression and for their molecular subtypes (Luminal type vs Basal type, assessed by BluePrintโ„ข molecular subtyping assay). In addition, we assessed the recurrence risk (low vs high) using the 70-gene MammaPrintโ„ข signature. We found that 55 out of 2,658 (2.1 %) tumors that are ERฮฑ positive by mRNA analysis also demonstrate a Basal molecular subtype, indicating that they lack expression of estrogen-responsive genes. These ERฮฑ-positive Basal-type tumors express significantly lower levels of both ERฮฑ and PR mRNA as compared to Luminal-type tumors (P < 0.0001) and almost invariably (94.5 %) have a high-risk MammaPrintโ„ข profile. Twelve of the MammaPrintโ„ข genes are directly ERฮฑ responsive, indicating that MammaPrintโ„ข assesses ERฮฑ function in breast cancer without considering ERฮฑ mRNA levels. We find a relatively high expression of the dominant negative ERฮฑ splice variant ERฮ”7 in ERฮฑ-positive Basal-type tumors as compared to ERฮฑ-positive Luminal-type tumors (P < 0.0001). Expression of the dominant negative ERฮฑ variant ERฮ”7 provides a rationale as to why tumors are of the Basal molecular subtype while staining ERฮฑ 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 MammaPrintโ„ข high recurrence risk and might benefit from adjuvant chemotherapy.

Read more: Groenendijk_2013_BCRT_Exon7 Deletion