A new oncogene that predicts breast cancer response to anti-estrogenic therapies

Breast cancer is the most prevalent cancer in females globally and including Singapore. The female sex hormone, estrogen, possesses a pivotal role, both in the initiation and progression of breast cancer, with the majority of human breast cancers being initially estrogen dependent. These estrogen dependent breast cancers are defined as estrogen receptor positive (ER+) breast cancers as they express the receptor for estrogen (ERα).

Patients with ER+ breast cancer are usually given anti-estrogenic drugs after surgery or radiation in an effort to prevent recurrence of the disease. Anti-estrogen based therapeutics, such as Tamoxifen and Fulvestrant or aromatase inhibitors, remain the primary adjuvant intervention for these patients with ER+ breast cancer. Despite the success of these anti-estrogenic therapies, a significant proportion (up to 50%) of patients with ER+ breast cancer develop relapses which are often fatal. The acquired resistance to continued anti-estrogenic therapy therefore presents a major obstacle for the improved clinical management of ER+ breast cancer. Clearly, patients with ER+ breast cancer treated with anti-estrogens, and at high risk of relapse, would benefit from additional early therapy. However, there is a paucity of reliable biomarkers to predict responses to anti-estrogen therapy in ER+ breast cancer and it remains a need to improve clinical management of ER+ breast cancer.

In an effort to address these issues, in a large collaborative effort between Singapore, New Zealand, China and the United Kingdom, Peter Lobie from CSI Singapore and colleagues have identified a novel secreted oncogene regulated by estrogen in breast cancer, and which predicts patient response to anti-estrogen therapies. The work was published in the December 2013 issue of Cancer Research. This novel oncogene is only present in hominoids and was named SHON standing for Secreted Hominoid specific ONcogene.

pl20141The new oncogene was observed to promote ER+ breast cancer cell growth and invasiveness and tumor growth in xenograft models. It was detected in more than 60% of breast cancers and its expression was positively correlated with ER positive cancer. In this setting, SHON expression predicted the response to anti-estrogen therapy in high-risk patients with ER+ breast cancer. The predictive ability of SHON appears to be specific for the response of ER+ patients to antiestrogens as it was not associated with patient survival outcomes in ER negative breast cancer nor response to anthracycline based chemotherapeutics. Hence, SHON may represent a simple biomarker to predict the therapeutic efficacy of anti-estrogen therapy in patients with ER+ breast cancer.

In addition to the utility as a biomarker for antiestogen responsiveness the authors also demonstrated that antibodies to SHON inhibited the cancer promoting functions of SHON, indicative that the secreted protein could also potentially serve as a therapeutic target for antibody based therapeutics.

Further work is needed to fully understand how SHON promotes tumor growth and spread, the involvement of SHON in the development of anti-estrogenic resistance and to fully determine its potential utility as a predictive biomarker or therapeutic target in ER+ breast cancer..