Zinc transporter LIV1: A promising cell surface target for triple negative breast cancer

Saravanan, Roshni; Balasubramanian, Vaishnavi; Balamurugan, Srikanth Swamy Swaroop; Ezhil, Inemai; Afnaan, Zeba; John, Jisha; Sundaram, Sandhya; Gouthaman, Shanmugasundaram; Pakala, Suresh B.; Rayala, Suresh K.; Venkatraman, Ganesh

doi:10.1002/jcp.30880

Cited by 6 publications

(12 citation statements)

References 118 publications

(221 reference statements)

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“…In this article, we focus on the target LIV1, which is the first zinc ion transporter protein found in breast cancer cells that can be induced by estrogen to be expressed, so it is thought to be closely associated with breast cancer development and progression. 3 24 25 26 Moreover, LIV1 is highly expressed in a variety of tumor cells including breast, prostate, pancreatic, cervical, and liver cancers with limited expression in normal tissues, 9 and this differential expression level makes LIV1 an ideal target for the development of ADCs.…”

Section: Discussionmentioning

confidence: 99%

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A Potential Antibody–Drug Conjugate Targeting Human LIV1 for the Treatment of Triple-Negative Breast Cancer

Zhang,

Liu,

Zhuang

et al. 2023

Pharmaceutical Fronts

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Triple-negative breast cancer (TNBC), which accounts for 15 to 20% of incidents of breast cancer, is the only breast cancer subtype that lacks targeted treatments. It was reported in the literature that LIV1 was highly expressed in TNBC and other solid tumors. This makes LIV1 a potential target for the treatment of TNBC. This study aimed to develop an anti-LIV1 antibody for the treatment of TNBC. In this study, a novel anti-LIV1 antibody Ab1120 was developed and conjugated with monomethyl auristatin E (MMAE) to obtain the antibody–drug conjugate, Ab1120-vcMMAE. The Cell Counting Kit-8 method was used to assess the killing effect of the antibody–drug conjugate on cell lines MDA-MB−231 (high LIV1 expression of breast cancer cell line), MDA-MB-468 (low LIV1 expression of breast cell line), and 293C18 (LIV1-negative human embryonic kidney cell). The antitumor effect of Ab1120-vcMMAE on an MDA-MB-231 xenograft model was determined by evaluating the tumor volume and body weight after its treatment. In vitro analysis showed that Ab1120-vcMMAE is a potent inhibitor against the proliferation of a LIV1 overexpression cell line. The in vivo results demonstrated its antitumor activity in the cell-derived xenograft breast tumor mouse model. The results of this study suggest that Ab1120-vcMMAE may be used as a new therapeutic drug for patients with LIV1 high-expression breast cancer.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

A Potential Antibody–Drug Conjugate Targeting Human LIV1 for the Treatment of Triple-Negative Breast Cancer

Zhang,

Liu,

Zhuang

et al. 2023

Pharmaceutical Fronts

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“…Multiple zinc transporters collectively help in maintaining zinc homeostasis in mammary epithelial cells [ 28 ]. ZIP6 was identified during genetic screening for the estrogen response factors in breast cancer tissues and was regarded as an estrogen-regulated gene, which was positively linked to the estrogen receptor (ER) [ 26 ]. Therefore, it has been highlighted that a high ZIP6 expression is a reliable marker of luminal A subtypes in breast cancer [ 29 ].…”

Section: Zinc Transporters and Breast Cancermentioning

confidence: 99%

“…The transporter-mediated imbalance of intracellular zinc can contribute to the development and progression of breast cancer. Reproduced with permission [ 26 ]. Copyright © 2022 Wiley Periodicals LLC.…”

Section: Figurementioning

confidence: 99%

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A Systematic Study on Zinc-Related Metabolism in Breast Cancer

Liu

Kong

et al. 2023

Nutrients

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Breast cancer has become the most common cancer worldwide. Despite the major advances made in the past few decades in the treatment of breast cancer using a combination of chemotherapy, endocrine therapy, and immunotherapy, the genesis, treatment, recurrence, and metastasis of this disease continue to pose significant difficulties. New treatment approaches are therefore urgently required. Zinc is an important trace element that is involved in regulating various enzymatic, metabolic, and cellular processes in the human body. Several studies have shown that abnormal zinc homeostasis can lead to the onset and progression of various diseases, including breast cancer. This review highlights the role played by zinc transporters in pathogenesis, apoptosis, signal transduction, and potential clinical applications in breast cancer. Additionally, the translation of the clinical applications of zinc and associated molecules in breast cancer, as well as the recent developments in the zinc-related drug targets for breast cancer treatment, is discussed. These developments offer novel insights into understanding the concepts and approaches that could be used for the diagnosis and management of breast cancer.

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Expression of cell surface zinc transporter LIV1 in triple negative breast cancer is an indicator of poor prognosis and therapy failure

Saravanan,

Balasubramanian,

Sundaram

et al. 2024

Journal Cellular Physiology

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Triple negative breast cancers (TNBC) are an aggressive molecular subtype of breast carcinoma (BC) identified by the lack of receptor expression for estrogen, progesterone, & human epidermal growth factor receptor‐2. Lack of tangible drug targets warrants further research in TNBC. LIV1, is a zinc (Zn) transporter known to be overexpressed in few cancer types including BCs. Recently, in the United States of America, FDA approved the use of a new drug targeting LIV1, antibody drug conjugate SGN‐LIV1A for treatment of TNBC patients. Though LIV1 also has a role in modulating immune cells by its differential transport of Zn, a correlation between the tumor cell expression of LIV1 and immune cell infiltrations were scantily reported. Further adequate baseline data on LIV1 expression in other populations have not been documented. Our objective was to screen a large Indian cohort of TNBC patient samples for LIV1, categorize the immune cell infiltration using CD4/CD8 expression and correlate the findings with therapy outcomes. Further, we also investigated for LIV1 expression in matched samples of primary & secondary tumors; pre & postchemotherapy in TNBC patients. Results showed an elevated expression of LIV1 in TNBC samples as compared to adjacent normal, the mean Q scores being 183.06 ± 6.39 and 120.78 ± 7.37 (p < 0.0001), respectively. Similarly, LIV1 levels were elevated in secondary tumors than primary & in patient samples postchemotherapy as compared to naïve. In the TNBC cohort, using automated method, cell morphology parameters were computed and analysis showed LIV1 levels were elevated in grade 3 TNBC samples presenting with altered cell morphology parameters namely cell size, cell perimeter, & nucleus size. Thus indicating LIV1 expressing TNBC samples portrayed an aggressive phenotype. Finally, TNBC patients with 3+ staining intensity showed poor survival (4.44 year) as compared to patients with 2+ LIV1 expression (5.47 year), emphasizing that LIV1 expression is a poor prognostic factor in TNBC. In conclusion, the study reports elevated expression of LIV1 in a large Indian TNBC cohort; high expression is a poor prognostic factor and correlated with aggressive disease and indicating the need for LIV1 targeted therapies.

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Zinc transporter LIV1: A promising cell surface target for triple negative breast cancer

Cited by 6 publications

References 118 publications

A Potential Antibody–Drug Conjugate Targeting Human LIV1 for the Treatment of Triple-Negative Breast Cancer

A Potential Antibody–Drug Conjugate Targeting Human LIV1 for the Treatment of Triple-Negative Breast Cancer

A Systematic Study on Zinc-Related Metabolism in Breast Cancer

Expression of cell surface zinc transporter LIV1 in triple negative breast cancer is an indicator of poor prognosis and therapy failure

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