Kinesin Family Member C1 (KIFC1/HSET): A Potential Actionable Biomarker of Early Stage Breast Tumorigenesis and Progression of High-Risk Lesions.

Victoria Seewaldt,Padmashree Rida,Zhihong Gong,Rick Kittles,Tijana Jovanovic-Talisman,Mark Labarge,Rama Natarajan,Nikita Wright

doi:10.3390/jpm11121361

Abstract

The enigma of why some premalignant or pre-invasive breast lesions transform and progress while others do not remains poorly understood. Currently, no radiologic or molecular biomarkers exist in the clinic that can successfully risk-stratify high-risk lesions for malignant transformation or tumor progression as well as serve as a minimally cytotoxic actionable target for at-risk subpopulations. Breast carcinogenesis involves a series of key molecular deregulatory events that prompt normal cells to bypass tumor-suppressive senescence barriers. Kinesin family member C1 (KIFC1/HSET), which confers survival of cancer cells burdened with extra centrosomes, has been observed in premalignant and pre-invasive lesions, and its expression has been shown to correlate with increasing neoplastic progression. Additionally, KIFC1 has been associated with aggressive breast tumor molecular subtypes, such as basal-like and triple-negative breast cancers. However, the role of KIFC1 in malignant transformation and its potential as a predictive biomarker of neoplastic progression remain elusive. Herein, we review compelling evidence suggesting the involvement of KIFC1 in enabling pre-neoplastic cells to bypass senescence barriers necessary to become immortalized and malignant. We also discuss evidence inferring that KIFC1 levels may be higher in premalignant lesions with a greater inclination to transform and acquire aggressive tumor intrinsic subtypes. Collectively, this evidence provides a strong impetus for further investigation into KIFC1 as a potential risk-stratifying biomarker and minimally cytotoxic actionable target for high-risk patient subpopulations.

Highlights

Black/African-American women disproportionately present in the clinic with the most aggressive breast tumor subtypes, such as basal-like and triple-negative breast cancers (TNBC) [1,3,4]
When cultured human mammary epithelial cells (HMECs) that carried genes encoding SV40 large-T antigen, the telomerase catalytic subunit, and H-ras oncoprotein were xenografted into immunocompromised mice, they developed into tumors that were poorly differentiated and infiltrated adjacent tissue [51]
These findings suggest that most transformed HMECs have already bypassed this barrier and can acquire malignant features after the addition of one strong oncogene, which can confer their ability to invade in vivo or develop into invasive carcinoma (IC)

Summary

Introduction

The critical molecular events underlying the development of each stage, known as aging, have been shown to primarily involve the bypassing of three distinct tumor-suppressive barriers in human mammary epithelial cells (HMECs), including stress-associated stasis, replicative senescence, and oncogene-induced senescence [10,11,12]. KIFC1 inhibition, which selectively targets cells harboring CA, has been shown to be an effective minimally cytotoxic anticancer strategy in preclinical studies [37] This finding suggests that KIFC1 inhibitors may be a potential treatment option for high-risk patients with premalignant or pre-invasive lesions to prevent progression. We encourage future investigation into this role to support the implementation of KIFC1 into routine clinical practice for high-risk patient subpopulations

From the Beginning

Bypassing the Stress-Associated Stasis Barrier

Bypassing the Replicative Cellular Senescence Barrier

Bypassing the Oncogene-Induced Senescence Barrier

Luminal or Basal-like

Future of Breast Cancer Risk Management