Breast cancers in AA women are characterized by earlier onset, higher aggressiveness, more extensive metastases, and increased mortality rates compared to those in Caucasian women. A bewildering mystery confronting clinicians and cancer cell biologists alike is why some non-invasive breast cancers transform into aggressive tumors that readily metastasize to distant sites in the body. A simple and reliable test to predict metastatic risk in early-stage tumors has so far remained elusive. Clearly, the critical barrier to progress is a lack of knowledge of quantifiable properties of non-invasive lesions that predict the probability of faster kinetic progression to metastatic disease. Our goal is to address this vital knowledge gap by identifying cell biological characteristics underlying the disease's aggressiveness, thereby reducing the breast cancer-related health disparity between African American (AA) and Caucasian women. Our central hypothesis states that amplified centrosomes enhance cell polarization by organizing a compacted Golgi network that propels directed cell migration and invasion to accelerate metastases. The tantalizing possibility that organellar-level disparities may exist between tumors of differing metastatic potential has never been explored. Our novel paradigm that CA promotes metastasis is a groundbreaking conceptual advancement, which holds translational promise in early risk prediction. Our project will enhance understanding of 1) cell-biological traits of non-invasive lesions that determine metastatic risk, and 2) mechanisms by which cells acquire migratory and invasive capabilities that underlie metastases. The impact of our study will be on the development of 1) rapid, non-invasive centrosome-based detection methods (e.g. fine-needle aspirate cytology) which will allow early distinction between clinically-indolent and potentially fatal breast cancers, thus saving patients with indolent disease from unnecessary mastectomy, b) a method for early stratification of patients into subgroups with distinct centrosomal profiles, for effective risk-adapted treatment of breast cancer, c) a framework for improving success rate of clinical trials involving investigational drugs by establishing new criteria for patient classification.
AIM 1 will establish differences in the incidence and severity of centrosome amplification between receptor- and grade-matched breast tumors from African American and Caucasian women.
AIM 2 will determine molecular mechanisms that link amplified centrosomes to more aggressive tumor phenotypes.
AIM 3 will pre-clinically develop small-molecule centrosome-targeted therapies for aggressive breast cancers, which will particularly benefit AA women, and reduce ethnic disparity in disease outcomes.

Public Health Relevance

It is perplexing as to why breast cancers in African American (AA) women are associated with a more aggressive clinical course and poorer survival than in Caucasian women. A critical barrier to progress in treating breast cancer is a lack of knowledge of quantifiable properties of non-invasive lesions that predict the probability of their faster kintic progression to metastatic disease. Our goal is to address this vital knowledge gap by identifying cell biological characteristics underlying the disease's aggressiveness, thereby paving the way to reducing the breast cancer-related health disparity between African American (AA) and Caucasian women. Our project will enhance understanding of 1) cell-biological traits of non-invasive lesions that determine metastatic risk, and 2) mechanisms by which cells acquire migratory and invasive capabilities that underlie metastases. The impact of our study will be on the development of a) non-invasive and quantitative centrosome-based detection methods (e.g. fine-needle aspirate cytology) which may allow early distinction between indolent and potentially fatal breast cancers, thus saving patients with indolent disease from unnecessary mastectomy, and b) a method for early stratification of patients into subgroups with distinct centrosomal profiles, for effective risk-adapted treatment of breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA179671-02
Application #
8930931
Study Section
Special Emphasis Panel (ZRG1-OBT-J (55))
Program Officer
Sharman, Anu
Project Start
2014-09-22
Project End
2019-08-31
Budget Start
2015-09-01
Budget End
2016-08-31
Support Year
2
Fiscal Year
2015
Total Cost
$307,100
Indirect Cost
$99,600
Name
Georgia State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
837322494
City
Atlanta
State
GA
Country
United States
Zip Code
30302
Mittal, Karuna; Choi, Da Hoon; Ogden, Angela et al. (2017) Amplified centrosomes and mitotic index display poor concordance between patient tumors and cultured cancer cells. Sci Rep 7:43984
Mittal, Karuna; Donthamsetty, Shashi; Kaur, Ramneet et al. (2017) Multinucleated polyploidy drives resistance to Docetaxel chemotherapy in prostate cancer. Br J Cancer 116:1186-1194
Saxena, Roopali; Yang, Chunhua; Rao, Mukkavilli et al. (2017) Preclinical Development of a Nontoxic Oral Formulation of Monoethanolamine, a Lipid Precursor, for Prostate Cancer Treatment. Clin Cancer Res 23:3781-3793
Ogden, Angela; Rida, Padmashree C G; Aneja, Ritu (2017) Prognostic value of CA20, a score based on centrosome amplification-associated genes, in breast tumors. Sci Rep 7:262
Klimov, Sergey; Rida, Padmashree Cg; Aleskandarany, Mohammed A et al. (2017) Novel immunohistochemistry-based signatures to predict metastatic site of triple-negative breast cancers. Br J Cancer 117:826-834
Ogden, Angela; Rida, Padmashree C G; Aneja, Ritu (2017) Centrosome amplification: a suspect in breast cancer and racial disparities. Endocr Relat Cancer 24:T47-T64
Ogden, Angela; Garlapati, Chakravarthy; Li, Xiaoxian Bill et al. (2017) Multi-institutional study of nuclear KIFC1 as a biomarker of poor prognosis in African American women with triple-negative breast cancer. Sci Rep 7:42289
Mittal, Karuna; Choi, Da Hoon; Klimov, Sergey et al. (2016) A centrosome clustering protein, KIFC1, predicts aggressive disease course in serous ovarian adenocarcinomas. J Ovarian Res 9:17
Xie, Songbo; Ogden, Angela; Aneja, Ritu et al. (2016) Microtubule-Binding Proteins as Promising Biomarkers of Paclitaxel Sensitivity in Cancer Chemotherapy. Med Res Rev 36:300-12
Pannu, Vaishali; Rida, Padmashree C G; Ogden, Angela et al. (2015) HSET overexpression fuels tumor progression via centrosome clustering-independent mechanisms in breast cancer patients. Oncotarget 6:6076-91

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