A. N. DIBA

CLINMEDICINE

A

Cancer

Killer?

Virus

Could

Potentially

Destroy

Ovarian

And

Breast

Cancer

27 Nov 2020

On Tue, November 24, 2020, 5: the YAHOO "yahoo.com" published a report entitled "A cancer killer? Canadian researcher wins award for virus that could potentially destroy ovarian and breast cancer" written by Elisabetta Bianchini.

The author of this research report writes the following:

"In the midst concerns about surgeries and treatments being impacted by the stress COVID-19 is having on Canada’s health care system, a Canadian researcher is being recognized by Mitacs for engineering cancer-killing viruses to treat breast and ovarian cancer."

In an interview with Yahoo Canada Taylor Jamieson-Datzkiw, MD-PhD student at the University of Ottawa says:

"The work that I specifically am doing is looking at breast and ovarian cancers that have become resistant to conventional drug therapy and making viruses that can hopefully overcome the resistance."

Source:

A
cancer
killer?
Canadian
researcher
wins
award
for
virus
that
could
potentially
destroy
ovarian
and
breast
cancer

Elisabetta Bianchini writes, "Her work, explained as “a new option for those patients who’ve run out of options,” involves manipulating viruses at the genetic level."

"They target the tumour, alter the expression of cancer cells and surrounding cells, and alert the individual’s immune system that a tumour exists."

In the interview with the reporter of YAHOO CANADA Jamieson-Datzkiw says, "Cancer is such a complex disease and I find it so interesting just knowing that there's so much work to be done."

"There's a lot of research being done for different chemotherapeutic drugs out there but I just thought it was so cool to come up with these personalized ways that we can treat tumours.”

Source:

A
cancer
killer?
Canadian
researcher
wins
award
for
virus
that
could
potentially
destroy
ovarian
and
breast
cancer

Elisabetta Biancini in her report addresses, "She explained that the most immediate steps are to try out the viruses in mice to see if they work in different models. The longer term goal for Jamieson-Datzkiw is to reach clinical trials."

Jamieson Datzkiw in this interview explains, "Whether or not my viruses will actually make it there will be decided upon if they're safe in mice and if they're effective in mice."

"We have to do a lot of trials before we can begin to decide if it's worth trying in a person, but...the goal is always to try to figure out something that can be translated to patients."

The reporter of this report notes:

"Jamieson-Datzkiw has earned the Mitacs Award for Outstanding Innovation — Indigenous Award, and is studying under Carolina Ilkow and John Bell at the University of Ottawa’s Faculty of Medicine’s Department of Biochemistry, Microbiology and Immunology and the Ottawa Hospital Research Institute."

Elisabetta Biancini writes, "She commended Mitacs for including this category in their awards, which also considered each individual’s involvement in the Indigenous community."

The reporter informs, "Jamieson-Datzkiw revealed that it’s hard to find Indigenous role models.

Jamieson-Datzkiew explains:

"I really appreciate that they kind of took into account that as an Indigenous researcher, you're not just an Indigenous person who's doing research but you also have an impact on your community."

"I had a really tough time finding mentors along the way and by kind of getting my name out there and saying, ‘hey, this is an Indigenous student who is a leader,’ then maybe it will allow other Indigenous students to reach out to me to ask me for mentorship."

Source:

A
cancer
killer?
Canadian
researcher
wins
award
for
virus
that
could
potentially
destroy
ovarian
and
breast
cancer

BRCA1

DEFICIENCY

PRMOTES

INFLAMMSOME

ACTIVITION

AND

MAMMRY

TUMOR

METASTASIS

12 Nov 2020

The 14 February 2020 issue of Advanced Science (vol.7 issue 6) published an article entitled "BRCA1 Deficiency Impairs Mitophagy and Promotes Inflammasome Activation and Mammary Tumor Metastasis" written by Qiang Chen, Josh Haipeng Lei,Jiaolin Bao,Haitao Wang, Wenhui Hao,Licen Li, Cheng Peng,Takaaki Masuda, Kai Miao,Jun Xu,Xiaoling Xu, Chu‐Xia Deng.

Source:

BRCA1
Deficiency
Impairs
Mitophagy
and Promotes
Inflammasome
Activation
and Mammary
Tumor
Metastasis

In an abstract Qiang Chen et al write the following:

"The breast cancer susceptibility gene 1 (BRCA1) is a major tumor suppressor gene and is most frequently mutated in hereditary breast cancer."

The authors address, "BRCA1 plays a critical role in many biological processes, especially maintaining genomic stability in the nucleus, yet its role in the cytoplasm remains elusive."

"Here," the writers note, "it is revealed that BRCA1 maintains a healthy mitochondrial network through regulating mitochondrial dynamics, including fission and fusion."

Source:

BRCA1
Deficiency
Impairs
Mitophagy
and Promotes
Inflammasome
Activation
and Mammary
Tumor
Metastasis

According to this abstract written bt Qiang Chen et al, "BRCA1 deficiency causes dysfunctional mitochondrial dynamics through increased expression of mitofusin1/2."

The authors go on to inform, "With mitochondrial stress, BRCA1 is recruited to the mitochondrial outer membrane, where it plays an essential role in maintaining a healthy mitochondrial network."

"Consequently," the writers address, "BRCA1 deficiency impairs stress‐induced mitophagy through blocking ataxia‐telangiectasia mutated (ATM)‐AMP‐activated protein kinase (AMPK)‐Dynamin‐related protein 1 (DRP1)‐mediated mitochondrial fission and triggers NLRP3 inflammasome activation, which creates a tumor‐associated microenvironment, thereby facilitating tumor proliferation and metastasis."

Source:

BRCA1
Deficiency
Impairs
Mitophagy
and Promotes
Inflammasome
Activation
and Mammary
Tumor
Metastasis

The authors write, "It is further shown that inflammasome inhibition can prevent tumor recurrence and metastasis."

The writers point out, "It is further shown that inflammasome inhibition can prevent tumor recurrence and metastasis."

The authors address, "This study uncovers an important role of BRCA1 in regulating mitophagy and suggests a therapeutic approach for fighting this deadly disease."

Source:

BRCA1
Deficiency
Impairs
Mitophagy
and Promotes
Inflammasome
Activation
and Mammary
Tumor
Metastasis

In the introduction of this article, the authors cite the paper of R. L. Siegel, K. D. Miller, A. Jemal, Ca‐ Cancer J. Clin. 2019, 69, 7. and write:

"Breast cancer is the most common disease in women, which accounts for 30% of all new cancers."

R. L. Siegel, K. D. Miller, A. Jemal, Ca‐Cancer J. Clin. 2019, 69, 7.

Source:

BRCA1
Deficiency
Impairs
Mitophagy
and Promotes
Inflammasome
Activation
and Mammary
Tumor
Metastasis

The writers cite an article from W. D. Foulkes, I. E. Smith, J. S. Reis‐Filho ( N. Engl. J. Med. 2010, 363, 1938) and address:

"The clinical and molecular heterogeneity of breast cancer is well known. Based on molecular classification, triple‐negative breast cancer (TNBC), which lacks expression of estrogen receptor (ER), progesterone receptor (PR), and Her2, accounts for ≈12–17% of breast cancer."

Triple-negative
breast cancer.
William D Foulkes
et al.
N Engl J Med. 2010

The authors cite the work of G. Bianchini, J. M. Balko, I. A. Mayer, M. E. Sanders, L. Gianni (Nat. Rev. Clin. Oncol. 2016, 13, 674) and write:

"Patients with TNBC have a relatively poorer prognosis compared with those with other breast cancer subtypes; this is due to its aggressive clinical properties and lack of established molecular targets for therapy."

Triple-negative
breast cancer:
challenges and
opportunities of
a heterogeneous
disease Giampaolo
Bianchini et al.
( Nat Rev Clin Oncol.
2016 Nov)

"Therefore, there has been an intense interest in finding new medications that can treat TNBC."

Source:

BRCA1
Deficiency
Impairs
Mitophagy
and Promotes
Inflammasome
Activation
and Mammary
Tumor
Metastasis

The writers explain, "The breast cancer susceptibility gene 1 (BRCA1) is a major breast cancer suppressor gene, which encodes a protein critical for maintaining DNA integrity and genomic stability."

Qiang Chen et al cite the work of S. Bayraktar, A. M. Gutierrez‐Barrera, D. Liu, T. Tasbas, U. Akar, J. K. Litton, E. Lin, C. T. Albarracin, F. Meric‐Bernstam, A. M. Gonzalez‐Angulo, G. N. Hortobagyi, B. K. Arun (Breast Cancer Res. Treat. 2011, 130, 145) and write:

"More than 75% of tumors developing in women who carry BRCA1mutations are TNBC."

Outcome of
triple-negative
breast cancer
in patients
with or
without
deleterious
BRCA
mutations
Soley Bayraktar
et al.
(Breast Cancer
Res Treat.
2011 Nov.)

The authors cite the works of C. X. Deng (Nucleic Acids Res. 2006, 34, 1416) and J. Dine, C. X. Deng, (Cancer Metastasis Rev. 2013, 32, 25) and write:

"BRCA1 tumor suppressor activity," write the authors, "has been attributed to its nuclear localization, where it participates in signaling pathways for DNA damage repair, transcription regulation, chromatin remodeling, cell cycle checkpoint control, and apoptosis."

***
Chu-Xia Deng.
Nucleic
Acids Res.
2006.
BRCA1:
cell
cycle
checkpoint,
genetic
instability,
DNA
damage
response
and
cancer
evolution

***
Jennifer Dine
et al.
( Cancer
Metastasis Rev.
2013 Jun.)
Mouse models
of BRCA1
and their
application
to
breast
cancer
research

Source:

BRCA1
Deficiency
Impairs
Mitophagy
and Promotes
Inflammasome
Activation
and Mammary
Tumor
Metastasis

The writers cite the paper of J. A. Rodriguez, B. R. Henderson ( J. Biol. Chem. 2000, 275, 38589) and note:

"Meanwhile, BRCA1 has been identified as a protein that shuttles between the nucleus and the cytoplasm."


J A Rodríguez
et al.
(J Biol Chem.
2000)
Identification of
a
functional
nuclear
export
sequence in
BRCA1

The scientists (Qiang Chen et al) cite the paper of J. Jiang, E. S. Yang, G. Jiang, S. Nowsheen, H. Wang, T. Wang, Y. Wang, D. Billheimer, A. B. Chakravarthy, M. Brown, B. Haffty, F. Xia (Cancer Res. 2011, 71, 5546) and write:

"Nuclear export of BRCA1 could be induced by DNA damage in the p53 dependent mechanism."


Juhong
Jiang
et al.
(Cancer Res.
2011):
p53-
dependent
BRCA1
nuclear
export
controls
cellular
susceptibility
to
DNA
damage

"However, the function of BRCA1 in cytoplasmic processes," the writers explain, "which may be independent from maintenance of genomic stability, is poorly understood."

Source:

BRCA1
Deficiency
Impairs
Mitophagy
and Promotes
Inflammasome
Activation
and Mammary
Tumor
Metastasis

The authors cite a 2018 article of S. Pickles, P. Vigie, R. J. Youle, (Curr. Biol. 2018, 28, R170) and explain:

"Mitochondria are crucial organelles for energy production and cellular homeostasis in mammalian cells; therefore, the maintenance of a healthy mitochondrial network is critical in the development as well as in the response to physiological adaptations and stress conditions throughout life."


Sarah Pickles
et al.
(Curr Biol.
2018):
Mitophagy
and <
Quality
Control
Mechanisms
in Mitochondrial
Maintenance

The writers note, "Mitophagy, a selective autophagic process, plays an important role in maintaining mitochondrial function."

Source:

BRCA1
Deficiency
Impairs
Mitophagy
and Promotes
Inflammasome
Activation
and
Mammary
Tumor
Metastasis

According to a citation from S. L. Archer (N. Engl. J. Med. 2013, 369, 2236) Qiang Chen et al (the authors of this investigation) write:

"Mitochondria as dynamic organelles are constantly undergoing fission and fusion, which are essential for regulation of mitophagy."


Stephen
L Archer
(N Engl J Med.
2013):
Mitochondrial
dynamics--
mitochondrial
fission
and
fusion
in
human
diseases

The authors refer to the works of J. W. Harper et al (2018), R. Zhou et al (2011) and S. Vyas et al (2016) address:

"Defects in mitophagy could lead to pathological conditions, such as neurodegeneration, inflammasome activation, and cancer."[*],[**], [***]

[*]
J. W. Harper,
A. Ordureau,
J. M. Heo Nat. Rev. Mol. Cell Biol.
2018, 19, 93.
"Building and decoding ubiquitin chains for mitophagy"
J Wade Harper et al.
Nat Rev Mol Cell Biol. 2018.
[**]
R. Zhou, A. S. Yazdi,
P. Menu,
J. Tschopp (Nature 2011,
469, 221).
Rongbin Zhou et al.
(Nature, 2011).
"A role for mitochondria
in NLRP3
inflammasome activation"
[***]
S. Vyas, E. Zaganjor,
M. C. Haigis
(Cell 2016, 166, 555)
Sejal Vyas et al.
Cell. 2016.
"Mitochondria and Cancer"

The writers point out, "Recent studies indicated that BRCA1 deficiency could impair oxidative phosphorylation and decrease ATP production in cardiac and muscle tissues,14-16 suggesting that BRCA1 is involved in mitochondrial functions."

"However, " write the authors, "little is known about how BRCA1 relates to mitophagy in response to mitochondrial damage and how defects in mitophagy contribute to BRCA1‐associated breast cancer."

Source:

BRCA1
Deficiency
Impairs
Mitophagy
and Promotes
Inflammasome
Activation
and Mammary
Tumor
Metastasis

Advanced Science:

Advanced Science
(14 February
2020,
vol. 7
issue 6):
BRCA1
Deficiency
Impairs
Mitophagy
and
Promotes
Inflammasome
Activation
and Mammary
Tumor
Metastasis

The same reference:

Advanced Science
(14 Feb. 2020, Vol.7 Issue 6)
BRCA1
Deficiency
Impairs Mitophagy
and
Promotes
Inflammasome
Activation
and Mammary
Tumor
Metastasis

Tumour

Suppressor

Genes

Are

The

Opposite

of

Oncogenes

18 Nov 2020

Author Matt Ridley in chapter 17 of his 1999 book (New York, Harper Colins) writes:

Tumour suppressors are the opposite of oncogenes." (p.235)

The author explains, "The body possesses genes whose job is to detect excessive growth and shut it down." (p.235)

"These genes, discovered first in the mid-1980s by Henry Harris in Oxford, are known as tumour-suppressor genes." (p 235)

The writer, "Tumour suppressors are the opposite of oncogenes."(p.235)

"Whereas oncogenes cause cancer if they are jammed on, writes the author, "tumour-suppressor genes cause cancer if they are jammed off." (p.235)

Matt Ridley (the author) continues," They do their jobs by various means, the most prominent of which is to arrest a cell at a certain point in its cycle of growth and division, then release it from arrest only if it has all its papers in order, so to speak." (p.235)

The writer addresses, "To progress beyond this stage,therefore, a tumour must contain a cell that has both a jammed-on oncogene and a jammed-off tumour-suporessor gene." (p 235)

"That is unlikely enough, but it is not the end of the matter," the author adds.(p.235)

He explains, "To escape and grow uncontrollably, the tumour must now pass by an even more determined checkpoint, manned by a gene that detects abnormal behaviour in a cell and issues an instruction to different genes to dismantle the cell from the inside: to commit suicide. This is TP53." (p.235)

The author addesses, "When TP53 was first discovered, by David Lane in Dundee in 1979, it was thought to be an oncogene, but it was later recognised to be a tumour suppressor."(p.235)

The writer informs, "Peter Hall offered his arm as a guinea pig for testing if TP53 was a tumour suppressor."(p.235)

The author adds, " Hall repeatedly scarred a small part of his arm with radiation and Lane took biopsies over the succeeding two weeks."(p.235)

"David Lane and his colleage Peter Hall," notes Matt Ridley, "after showed a dramatic rise in the level of p53, the protein manufactured from TP53, following the radiation damage, clear evidence that the gene responded to cancer-causing damage."(p.235)

"Lane has gone on," addresses the writer, "to develop p53 as a potential cancer cure in clinical trials; the first human volunteers will be taking the drug as this book is being published."(p.235)

The author explains, "Mutation in the TP53 gene is almost the defining feature of a lethal cancer; in fifty-five per cent of all human cancers, TP53 is broke."(p.236)

"The proportion rises to over ninety per cent among lung cancers," writes Matt Ridley in his 1999 book "Genome: The Authibiography of A Species in 23 Chapters.(p.236)