Women of African descent in the United States are twice as likely to develop triple-negative breast cancer (TNBC), compared to women of European descent. African American (AA) women with TNBC present a much more aggressive disease course relative to their European American (EA) counterparts. Thus, there is an urgent need to evaluate race-specific biomarkers and their molecular regulation to improve survival outcome in African American (AA)patients. Kinesin family member C1 (KIFC1), a minus-end-directed microtubule motor protein is involved in centrosomal clustering and chromosomal instability. KIFC1 is highly overexpressed (fold change=1.50, p=0.000392) in TNBC relative to non-TNBC. We previously showed that ablation of KIFC1 impaired proliferation and migration of AA TNBC cells to a greater extent than European American (EA) equivalent. Our published data also showed that the weighted index (WI) of nuclear KIFC1 (nKIFC1) is higher in AA TNBC (WI: 154.66 vs. 133.74, AA and EA, respectively, p = 0.036) and nKIFC1 is an independent poor prognosis biomarker exclusively for AA TNBC patients. While the centrosome clustering role of KIFC1 during mitosis is well-established, its predominant nuclear localization in interphase may underlie its previously unrecognized race-specific association. We and others have shown that nKIFC1 immunoprecipitates with various histones, helicases, and actinins. Immunoprecipitation (IP) of KIFC1 from nuclear fractions of TNBC cell lines followed by mass-spectrometry analysis revealed myosin heavy chain 9 (MYH9), a tumor suppressor protein that stabilizes p53 and promotes its nuclear retention, as the top nKIFC1 binding partner in AA TNBC cell lines (MDA-MB-468 and HCC1806). However, we observed a rather low affinity (rank 5th) or no binding of MYH9 with nKIFC1 in EA TNBC cell lines (MDA-MB-436, HCC1937). Our IP-MS data suggest that a) the relative abundance of MYH9 in nKIFC1 immunoprecipitates is higher in the AA TNBC cell lines and b) MYH9 expression is higher in AA TNBC compared to EA TNBC cells. We hypothesize that nKIFC1 impairs the tumor suppressor function of MYH9 more effectively in AA compared to EA TNBC cells. Intriguingly, KIFC1 immunoprecipitates also showed the presence of beta, alpha-, and gamma actin along with several dead box helicases such as DDX5, DDX17, exclusively in AA TNBC cell lines, suggesting that a combination therapy regimen of KIFC1 inhibitor (SR31527, CW069, and AZ82) and taxane/anthracycline/platinating agent might be more effective in AA than in EA TNBC cells. RNA seq analyses to identify other KIFC1partners using KIFC1 knock out using CRISPR-CAS9 approach in AA and EA TNBC cell lines are currently underway.
Citation Format: Chakravarthy Garlapati, Shriya Joshi, Luciane Cavalli, Uma Krishnamurti, Shobhna Kapoor, Ritu Aneja. Myosin heavy chain 9 (MYH9) is a novel interacting partner of kinesin family member C1 (KIFC1) in African American TNBC: Implications for racial disparity [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr A070.