Development of a novel biomarker and therapeutic target for breast cancer

Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death in women globally. Although remarkable improvements in prognosis and treatment of breast cancer have been made in the last two decades, significant challanges remain for curative treatment for breast cancer; these include frequent appearance of endocrine therapy resistance in estrogen receptor positive (ER+) breast cancer, heterogeneity in resistance to targeted therapy and over-treatment. Various mechanisms have been proposed to be implicated in the development of resistance the treatments, the factors involved appear to be highly complex and heterogeneous. Therefore, identification and functional characterization of novel biomarkers is essential to improve prediction of prognosis and guiding precise therapy for breast cancer patients; this is the main challenge faced by clinicians every day. Our study aimed to develop a new biomarker for prognosis and treatment of breast cancer. Our earlier studies demonstrated that the Six Transmembrane Protein of Prostate 1 (STAMP1) is increased in prostate cancer and promotes prostate cancer progression. In stark contrast to prostate cancer, we found that in breast cancer the expression of STAMP1 mRNA is significantly decreased and is significant inversely correlated with multiple clinical/pathological parameters including prognosis. We have therefore assessed (1) the potential of STAMP1 and its associated signature as biomarkers for breast cancer, and (2) whether STAMP1 is a potential regulator of ER signaling with implications for endocrine resistance. The research data obtained in this project are summarized as below. In this project, we have generated a STAMP1-related gene signature which displays comparable prognostic power for ER+ primary breast cancer patients compared with the well-established PAM50 gene signature. In addition, the association of STAMP1 protein expression with endocrine treatment response in breast cancer have been assessed in 3 cohorts of tissue microarrays (TMAs), and the results showed that STAMP1 expression significantly correlates with development of endocrine resistance in breast cancer. Overall, our data suggested differential prognostic roles of STAMP1 for breast cancer patients with primary disease or endocrine-resistant disease. Mechanistically, we have found that loss of STAMP1 resulted in activation of multiple oncogenic signaling pathway, including PI3K-AKT and ERα pathways. Our results showed that STAMP1 could interfere with signaling transduction of G-protein coupled receptor pathway. Loss of STAMP1 significantly sensitized the response of breast cancer T47D cells to the stimulation of prostaglandin E2, which promotes cell survival and migration through PTGER4. The effect of STAMP1 on breast cancer cell growth was also determined in vivo using xenograft mouse model. Depletion of STAMP1 in breast cancer cells in xenografts in nude mice resulted in slower tumor growth rate compared with the control, which is contradicting to the in vitro data. These results suggested an environment dependent effect of STAMP1 on breast cancer cells, of which the underlying molecular mechanisms remains unclear. In conclusion, we have assessed potential function of STAMP1 in ER+ breast cancer cells both in vitro and in vivo, as well as the association of STAMP1 expression with disease progression. Our data indicated a context-dependent role of STAMP1 in the pathogenesis of breast cancer, including a role in treatment resistance. Veronica Fitzpatrick Blihovde, PhD student supported by this project has conducted the major part of the experiments. Breast cancer is the most widely diagnosed and leading cause of cancer death in women. The disease has caused an enormous toll on society in terms of lives lost and significant healthcare costs. Estrogen receptor positive (ER+) breast cancer represents more than 70% of the total cases at diagnosis, and thus ER-targeted endocrine therapy is the mainstay of current treatment for majority of breast cancer patients. Although significant improvements in prognosis and treatment of ER+ breast cancer have been made, endocrine therapy resistance remains a significant challenge in the clinic. Up to date, there are few biomarkers that could predict response to endocrine treatment and there is a paucity of potential therapeutic targets. This project aimed to use STAMP1 and its related genes to develop a better prognostic/predictive tool for breast cancer diagnosis and treatment, as well as to understand its biological role in disease development. Our data also indicated that a STAMP1-related gene signature have potential utility in clinic. The results from the project have provided a good basis for a novel treatment strategy for endocrine resistance through inhibition of STAMP1 expression, which has a major impact once translated into the clinic. Knowledge from this study will help to improve the efficacy of treatment and thus improve health span of breast cancer patients, therefor will have a positive impact on patient care.