Molecular analysis reveals heterogeneity of mouse mammary tumors conditionally mutant for Brca1

Original tumors, serially transplanted and multiple cell lines derived from Brca1 mammary tumors were characterized by morphology, gene and protein expression, and cell surface markers.Gene expression among Brca1 tumors showed more heterogeneity than among previously characterized tumors from MMTV-PyMT and -Wnt1 models. Gene expression data segregated Brca1 tumors into 3 distinct types: basal, mixed luminal, and tumors with epithelial-to-mesenchymal transition (EMT). Serial transplantation of individual tumors and multiple cell lines derived from the original tumors recapitulated the molecular characteristics of each tumor of origin. One tumor had distinct features of EMT and gave rise to cell lines that contained a distinct CD44+/CD24-/low population that may correlate with human breast cancer stem cells.Although individual tumors expanded by transplantation maintain the genomic profile of the original tumors, the heterogeneity among Brca1 tumors limits the extent of their use for preclinical testing. However, cell lines offer a robust material for understanding tumor biology and response to therapies driven by BRCA1 deficiency.Breast cancer is the most common neoplastic disease in women and affects approximately 1 out of 10 females. Human breast cancer is a heterogeneous disease with varied clinical course [1,2]. Up to 5% breast cancer cases are attributable to inherited mutations in the BRCA1 or BRCA2 genes [3]. Inherited mutations of BRCA1 (chromosome 17q21) have been linked to increased risk for breast and ovarian cancers [4]. The BRCA1 tumor suppressor plays a major role in DNA damage, signaling, repair and cell cycle control. BRCA1 is also a co-regulator of steroid hormone receptors and modifies steroid hormone action [5]. Carriers of the mutant gene also have significantly higher risk for developing other tumor types, including ovarian, uterine, cervical, and prostate cancers [6]. Breast cancer patients with BRCA1 mutations are more likely to be estrogen rec