Loss of function of several known 'tumor suppressor' genes plays an important role in transformation to malignancy. We have shown that the retinoblastoma (RB) gene is one of these, and its dysfunction is found in many cancers besides retinoblastoma, including some breast cancers. Furthermore, normal Rb protein inhibits progression through the cell cycle, and in tumors with dysfunctional Rb, we have shown that restoration of functional Rb can reverse malignancy. We have now identified several new proteins which interact with Rb and which regulate the cell cycle at distinct points; clearly these could also function as tumor suppressors. In addition, the genes BRCA-1 and brush-1 (which may be BRCA-2) which are associated with familial breast cancer appear to be tumor suppressor genes, though their prevalence in non-familial breast cancer has not been established. We therefore propose to investigate the roles of all of these genes in human breast cancer, demonstrating prevalence, biological activity, relationship with progression and clinical outcome, and potential for therapeutic reversal of their dysfunction.
Our specific aims are: 1) To carry out genetic analyses of our newly characterized Rb-associated genes H-nuc, mitosin, and E2F-1 in breast cancer and paired normal tissues. For genes found to be mutated in breast cancer, we will define their biological actions in a tumor cell culture system. 2) To determine the biological significance of BRCA-1 and brush-1 mutations in the same system. 3) To prepare effective monoclonal antibodies against the H-nuc, mitosin, E2F-1, and BRCA-1 proteins for use in immunohistochemistry. 4) To detect these proteins and their mutations by immunostaining in a large series of human breast cancers and premalignant breast lesions of defined stages, in order to evaluate their association with known biomarkers, with probability of recurrence of primary breast cancer, and with evolutionary stage and cancer risk of premalignant lesions. 5) To explore the therapeutic power of an adenovirus vector carrying the normal RB gene and potentially some of the other tumor suppressor genes studied here to inhibit growth of tumors in which these genes are dysfunctional, using tumor xenograft models of both local (mammary fat pad) and locally advanced (malignant ascites) human breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA058183-05
Application #
5209186
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
1996
Total Cost
Indirect Cost
Kaochar, Salma; Mitsiades, Nicholas (2018) A Novel Mechanism to Drive Castration-Resistant Prostate Cancer. Trends Endocrinol Metab 29:366-368
Bhat, Raksha R; Yadav, Puja; Sahay, Debashish et al. (2018) GPCRs profiling and identification of GPR110 as a potential new target in HER2+ breast cancer. Breast Cancer Res Treat 170:279-292
Guarducci, Cristina; Bonechi, Martina; Benelli, Matteo et al. (2018) Cyclin E1 and Rb modulation as common events at time of resistance to palbociclib in hormone receptor-positive breast cancer. NPJ Breast Cancer 4:38
Rimawi, Mothaffar F; De Angelis, Carmine; Contreras, Alejandro et al. (2018) Low PTEN levels and PIK3CA mutations predict resistance to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2 over-expressing breast cancer. Breast Cancer Res Treat 167:731-740
Sukumaran, Sujita; Watanabe, Norihiro; Bajgain, Pradip et al. (2018) Enhancing the Potency and Specificity of Engineered T Cells for Cancer Treatment. Cancer Discov 8:972-987
Hertz, D L; Kidwell, K M; Hilsenbeck, S G et al. (2017) CYP2D6 genotype is not associated with survival in breast cancer patients treated with tamoxifen: results from a population-based study. Breast Cancer Res Treat 166:277-287
Yu, L; Liang, Y; Cao, X et al. (2017) Identification of MYST3 as a novel epigenetic activator of ER? frequently amplified in breast cancer. Oncogene 36:2910-2918
Guven, Adem; Villares, Gabriel J; Hilsenbeck, Susan G et al. (2017) Carbon nanotube capsules enhance the in vivo efficacy of cisplatin. Acta Biomater 58:466-478
Veeraraghavan, Jamunarani; De Angelis, Carmine; Reis-Filho, Jorge S et al. (2017) De-escalation of treatment in HER2-positive breast cancer: Determinants of response and mechanisms of resistance. Breast 34 Suppl 1:S19-S26
Xu, Xiaowei; De Angelis, Carmine; Burke, Kathleen A et al. (2017) HER2 Reactivation through Acquisition of the HER2 L755S Mutation as a Mechanism of Acquired Resistance to HER2-targeted Therapy in HER2+ Breast Cancer. Clin Cancer Res 23:5123-5134

Showing the most recent 10 out of 306 publications