File Download
Supplementary
-
Citations:
- Appears in Collections:
postgraduate thesis: Hyperpolarization-activated cyclic nucleotide-gated channels (HCNs) regulating apoptosis in breast cancer : a novel potential anti-cancer target
Title | Hyperpolarization-activated cyclic nucleotide-gated channels (HCNs) regulating apoptosis in breast cancer : a novel potential anti-cancer target |
---|---|
Authors | |
Advisors | Advisor(s):Khoo, US |
Issue Date | 2019 |
Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
Citation | Mok, K. C. [莫家俊]. (2019). Hyperpolarization-activated cyclic nucleotide-gated channels (HCNs) regulating apoptosis in breast cancer : a novel potential anti-cancer target. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. |
Abstract | Abstract of thesis entitled
“Hyperpolarization-activated cyclic nucleotide-gated channels (HCNs)
regulating apoptosis in breast cancer: A novel potential anti-cancer target.”
Submitted by
Ka Chun Mok
For the degree of Doctor of Philosophy at
The University of Hong Kong
in January 2019
Breast cancer is the most common female cancer globally. Amongst the major
subtypes of breast cancer based on the expression of receptor proteins, triple
negative breast cancer (TNBC) has the most adverse prognosis. The only effective
treatment options for these patients is chemotherapy which however cause
adverse side effects. From my work, I have found that overexpression of
hyperpolarization-activated cyclic nucleotide-gated channels (HCNs), members of
the voltage-gated cation channels family, was essential for modulating apoptotic
resistance in breast cancer cells. Cells exposed to apoptotic stimulus are induced
to hyperpolarize, the cytoplasm becoming negative charged. In normal cells, the
negative charge induced by hyperpolarization can switch on apoptosis signaling to
execute cell death. However, in breast cancer cells, the overexpressing HCN
channels mediate the influx of calcium and potassium ions to recover the charge
in the cytoplasm and elicits various cellular responses to avoid cell death. There
are four subtypes of HCN channels, HCN 1 to 4. In vitro study showed that only
HCN2 and HCN3 are expressed in the breast cancer cells. In vivo data from TCGA
database as well as my own analysis on the expression of HCN2 and HCN3 in
primary breast tumor of Chinese breast cancer patients on tissue microarray
(TMA), confirmed the overexpression of HCN2 and HCN3 in breast cancer
compared with normal breast epithelium.
Ivabradine, an FDA approved HCN channel blocker has been used clinically to
attenuate heart rate in patients with chronic angina. Due to the overexpression of
HCN2 and HCN3 in breast cancer cells, I proposed that Ivabradine could induce
apoptosis in these cells. By in vitro studies, I confirmed that Ivabradine could lead
to apoptotic cell death by inducing endoplasmic reticulum (ER)-stress as indicated
by nuclear translocation of ATF4 and CHOP and decreased proliferation as
indicated by downregulation of the NFAT signaling pathway, and decreased
translocation of nuclear NFATc1. Likewise, knockdown of these two HCN channels
resulted in apoptosis, due to ER-stress, and decreased proliferation due to
downregulation of the NFAT pathway.
I tested the effect of Ivabradine on xenograft mouse models constructed from
triple negative MDA-MB-231 and MDA-MB-453 cell lines. The results showed that
Ivabradine could suppress tumor growth as revealed by decreased tumor volume
and decreased proliferation rate. I further established xenograft models using
stable knockdown of HCN2 and HCN3 in the MDA-MB-231 cell line and confirmed
that knockdown of both HCN channels could suppress the growth of the breast
tumors in mice, induce ER stress and apoptosis and decrease proliferation.
Taken together, my findings have confirmed that HCN channels play an important
role in maintenance of tumorigenesis in breast cancer. Ivabradine, an FDA
approved drug, could be a novel drug used for targeted therapy in breast cancer
especially TNBC. My research work has therefore uncovered the roles of HCN
channels in breast cancer and identified a potential targeted therapy for TNBC. |
Degree | Doctor of Philosophy |
Subject | Breast - Cancer - Treatment Breast - Cancer Ivabradine |
Dept/Program | Pathology |
Persistent Identifier | http://hdl.handle.net/10722/285982 |
DC Field | Value | Language |
---|---|---|
dc.contributor.advisor | Khoo, US | - |
dc.contributor.author | Mok, Ka Chun | - |
dc.contributor.author | 莫家俊 | - |
dc.date.accessioned | 2020-08-25T08:43:50Z | - |
dc.date.available | 2020-08-25T08:43:50Z | - |
dc.date.issued | 2019 | - |
dc.identifier.citation | Mok, K. C. [莫家俊]. (2019). Hyperpolarization-activated cyclic nucleotide-gated channels (HCNs) regulating apoptosis in breast cancer : a novel potential anti-cancer target. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. | - |
dc.identifier.uri | http://hdl.handle.net/10722/285982 | - |
dc.description.abstract | Abstract of thesis entitled “Hyperpolarization-activated cyclic nucleotide-gated channels (HCNs) regulating apoptosis in breast cancer: A novel potential anti-cancer target.” Submitted by Ka Chun Mok For the degree of Doctor of Philosophy at The University of Hong Kong in January 2019 Breast cancer is the most common female cancer globally. Amongst the major subtypes of breast cancer based on the expression of receptor proteins, triple negative breast cancer (TNBC) has the most adverse prognosis. The only effective treatment options for these patients is chemotherapy which however cause adverse side effects. From my work, I have found that overexpression of hyperpolarization-activated cyclic nucleotide-gated channels (HCNs), members of the voltage-gated cation channels family, was essential for modulating apoptotic resistance in breast cancer cells. Cells exposed to apoptotic stimulus are induced to hyperpolarize, the cytoplasm becoming negative charged. In normal cells, the negative charge induced by hyperpolarization can switch on apoptosis signaling to execute cell death. However, in breast cancer cells, the overexpressing HCN channels mediate the influx of calcium and potassium ions to recover the charge in the cytoplasm and elicits various cellular responses to avoid cell death. There are four subtypes of HCN channels, HCN 1 to 4. In vitro study showed that only HCN2 and HCN3 are expressed in the breast cancer cells. In vivo data from TCGA database as well as my own analysis on the expression of HCN2 and HCN3 in primary breast tumor of Chinese breast cancer patients on tissue microarray (TMA), confirmed the overexpression of HCN2 and HCN3 in breast cancer compared with normal breast epithelium. Ivabradine, an FDA approved HCN channel blocker has been used clinically to attenuate heart rate in patients with chronic angina. Due to the overexpression of HCN2 and HCN3 in breast cancer cells, I proposed that Ivabradine could induce apoptosis in these cells. By in vitro studies, I confirmed that Ivabradine could lead to apoptotic cell death by inducing endoplasmic reticulum (ER)-stress as indicated by nuclear translocation of ATF4 and CHOP and decreased proliferation as indicated by downregulation of the NFAT signaling pathway, and decreased translocation of nuclear NFATc1. Likewise, knockdown of these two HCN channels resulted in apoptosis, due to ER-stress, and decreased proliferation due to downregulation of the NFAT pathway. I tested the effect of Ivabradine on xenograft mouse models constructed from triple negative MDA-MB-231 and MDA-MB-453 cell lines. The results showed that Ivabradine could suppress tumor growth as revealed by decreased tumor volume and decreased proliferation rate. I further established xenograft models using stable knockdown of HCN2 and HCN3 in the MDA-MB-231 cell line and confirmed that knockdown of both HCN channels could suppress the growth of the breast tumors in mice, induce ER stress and apoptosis and decrease proliferation. Taken together, my findings have confirmed that HCN channels play an important role in maintenance of tumorigenesis in breast cancer. Ivabradine, an FDA approved drug, could be a novel drug used for targeted therapy in breast cancer especially TNBC. My research work has therefore uncovered the roles of HCN channels in breast cancer and identified a potential targeted therapy for TNBC. | - |
dc.language | eng | - |
dc.publisher | The University of Hong Kong (Pokfulam, Hong Kong) | - |
dc.relation.ispartof | HKU Theses Online (HKUTO) | - |
dc.rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works. | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject.lcsh | Breast - Cancer - Treatment | - |
dc.subject.lcsh | Breast - Cancer | - |
dc.subject.lcsh | Ivabradine | - |
dc.title | Hyperpolarization-activated cyclic nucleotide-gated channels (HCNs) regulating apoptosis in breast cancer : a novel potential anti-cancer target | - |
dc.type | PG_Thesis | - |
dc.description.thesisname | Doctor of Philosophy | - |
dc.description.thesislevel | Doctoral | - |
dc.description.thesisdiscipline | Pathology | - |
dc.description.nature | published_or_final_version | - |
dc.date.hkucongregation | 2019 | - |
dc.identifier.mmsid | 991044264460603414 | - |