Identification of CGA as a novel estrogen receptor-responsive gene in breast cancer: An outstanding candidate marker to predict the response to endocrine therapy

The estrogen receptor (ER) status of breast tumors is used to identify pati ents who may respond to endocrine agents such as tamoxifen, However, ER sta tus alone is not perfectly predictive, and there is a pressing need for mor e reliable markers of endocrine responsiveness. Here, we identified the well-known CGA gene (coding for the alpha subunit o f glycoprotein hormones) as a new ER alpha -responsive gene in human breast cancer cells. We used a real-time quantitative reverse transcription-PCR a ssay to quantify CGA mRNA copy numbers in a large series of breast tumors. CGA overexpression (>10 SD above the mean for normal breast tissues) was ob served in 44 of 131 (33.6%) breast tumor RNAs, ranging from 20 to 16,500 ti mes the level in normal breast tissues; the highest levels of CGA gene expr ession were close to those observed in placenta. Significant links were observed between CGA gene overexpression and Scarff- Bloom-Richardson histopathological grade I+II (P = 0.015), and progesterone (P = 0.0009) and estrogen (P < 10(-7)) receptor positivity, which suggeste d that CGA is a marker of low tumor aggressiveness. We observed CGA mRNA ov erexpression in 44 of 90 (48.9%) ER<alpha>-positive tumors and in none of t he 41 ER alpha -negative tumors. Immunohistochemical studies demonstrated t hat human chorionic gonadotropin alpha protein was strictly limited to ER a lpha -positive tumor cells. Overexpression of the CGA gene was not accompan ied by overexpression of the CGB gene. Our results also suggest that CGA could be a more reliable marker than PS2 and PR for ER alpha functionality and, thus, for endocrine responsiveness. Moreover, the CGA marker has the added value of dichotomizing ER alpha -pos itive patients into two subgroups of similar size. Specific antibodies dire cted to secreted human chorionic gonadotropin a protein are commercially av ailable, thus facilitating the future application of this marker to the cli nical management of breast cancer.