LH receptor gene expression is essentially absent in breast tumor tissue: implications for treatment

Abstract

Worldwide, breast cancer is the most frequently occurring malignancy in women. Early age at full term pregnancy has a protective effect against breast cancer. Evidence coming from a rat breast cancer model suggests a possible role for the pregnancy hormone hCG, a ligand of the LH receptor, as a mediator for this effect. In a previous study, we found that a common polymorphism in the LH receptor associates with tumor progression in premenopausal breast cancer patients, as carriers of the variant receptor showed a shorter disease free survival compared to non-carriers. How hCG and its receptor exert their effects on breast cancer, however, is unclear. One possibility is that these effects take place through LH receptors present in the ovaries, thereby influencing steroid hormone production. Another possibility is that the effects take place through LH receptors present in breast tumor cells themselves, as some studies have detected the receptor in both normal and neoplastic breast tissues and in breast cancer cell lines. To investigate whether a direct effect of LH signaling in breast cancer is likely, we measured LH receptor mRNA expression levels in 1551 breast tumors and 42 different human breast cancer cell lines using a qRT-PCR with a wide dynamic range. In addition, associations between LH receptor expression and clinico-pathologic factors were investigated. Assay validation showed that as little as ?10 copies per reaction volume of LH receptor cDNA could still be detected by our assay. We show that LH receptors are undetectable in 62% of breast tumor samples and 41 of 42 breast cancer cell lines. For the remaining samples we found expression levels to be very low. Although low, expression of the LH receptor appears to be associated with normal breast cells, favorable tumor characteristics and low tumor percentage. Since expression of the LH receptor in breast cancer cells is very low, it almost excludes the possibility of direct signaling effects. We therefore conclude that signaling effects of the LH receptor on breast cancer most likely take place by an indirect pathway through the ovaries.

Figure 1

Cycle threshold values obtained by performing the LH receptor qRT-PCR on a dilution series of cDNA derived from the LH receptor expressing TRex-hLHR cell line (panel A) and a dilution series of plasmid DNA containing cDNA encoding the LH receptor (panel B). Values are presented as means ± SE. A straight line with slope held constant to −1/log2 (corresponding to a decrease of one Ct per two-fold increase in DNA content) was fitted through the data points.

Figure 2

LH receptor expression levels in 1551 human breast tumors. Pie chart shows the number of tumors within each category of expression (Panel A). Histograms show the expression levels for tumors in the ‘inconclusive’ (Panel B) and ‘detectable’ (Panel C) expression category. For comparison, the level of LH receptor expression as determined on a human testis specimen has been indicated by an arrow; marked with a ‘T’.