Germline mutation in NF1 causes Neurofibromatosis type 1, a common inherited disorder that predisposes individuals to both benign and malignant tumors of the nervous system1, as well as an increased risk for breast cancer. Analysis of TCGA data has shown that NF1 is mutated in a wide range of common cancers (e.g., melanoma, lymphoma, and cancers of the lung, breast, and colon). In this regard, NF1-deficiency underlies the formation and/or progression of a large number of cancers, as well as many neurological disorders, and the development of therapies targeted to NF1-deficient malignancies would have broad impact. NF1 loss induces tamoxifen resistance in ER+ breast cancer. Approximately 2/3 of all breast cancers (150,000 diagnosed annually) are dependent on estrogen receptor-α (ER) to grow. Although great strides have been made in targeting the ER pathway for treating this type of tumor, relapse and death is common and is closely linked to resistance to ER-targeting agents. As a result, the majority of deaths from breast cancer still come from ER+ tumors.
To discover drivers for endocrine resistance, we have sequenced tumor DNAs from a cohort of >600 patients treated by 5-year tamoxifen monotherapy with a median 10.4 years follow up. This is a valuable cohort for detecting genes involved in tamoxifen resistance because it is not confounded by simultaneous chemotherapies. It also has a long follow up of over 10 years (as compared to <4 years in TCGA), which is important because relapse risk for ER+ tumors extends over a very long period. Our preliminary data show that poor outcomes were selectively associated with NF1 mutations that caused protein truncations. We note that NF1 was also identified in an unbiased in vitro siRNA screen for drivers of tamoxifen resistance. In addition, in a previous study comparing mutations in primary versus metastatic breast cancers, NF1 loss was undetectable in primary but more common in metastatic breast cancer. This project centers on the NF1 (Neurofibromin 1) gene whose loss is proposed to induce aggressive tumor behavior (e.g., resistance to tamoxifen, a very common form of endocrine therapy) and relapse. As such, successful completion of the proposed study will address one overarching challenge “Identify what drives breast cancer growth; determine how to stop it.”