ABSTRACT

Cystic Fibrosis (CF) is an autosomal recessive disorder which is caused due to the
mutation ( F 508 ) in CFTR genes a glycoprotein which acts as a chloride channel and is
responsible for chloride ions transport in various epithelial tissues present highly in
Reproductive system, Lungs, Gastrointestinal system, Sweat glands etc., Recently It has been
studied that CFTR also has its role in Inflammation, apoptosis where it forms various
macromolecular complex by getting associated with proteins. Though Cystic Fibrosis mainly
affects lungs and pancreas, there are many gaining evidence to show a novel role of Cystic
Fibrosis in many Cancers especially in Breast Cancer where Cystic Fibrosis suppresses breast
cancer growth due to the presence of high ATP level in blood but also increases the cancer
metastasis due to same increased ATP levels in blood. The ATP binds to purinergic receptor
and shows both its tumour growth suppression action and its metastasis action. ATP makes
the study more interesting by its dual role and also it highlights the impacts of purinergic
receptor in cancer studies. This seems controversial but Cystic fibrosis may at least partially
reduces the pathological condition of Breast Cancer. By studying the complete mechanism
and by knowing the way how Cystic Fibrosis is able to inhibit breast cancer we may upgrade
our level and go closer to the step to cure Breast Cancer which is a major concern affecting 1
in 32 women according to the report from various national cancer registry. This also brings
interest in linking various cancers with different genetic variations of CFTR gene. The
following review will show the critical findings that links Cystic Fibrosis and Breast Cancer
along with the detailed mechanism between them. In Addition, the role of CF therapeutics in
Breast Cancer is proceeded. In Future, study of each disease with Cancer Biology along with
giving importance to purinergic receptor will leads to the new therapeutics that can pave a
new way for a diagnosis and treatments.
 INTRODUCTION

Cystic Fibrosis, a disorder due to the defective CFTR affects many in

Caucasian population. It is a 230kb protein which was identified in 1989 that primarily works
as chloride channel , ion channels modulator and transporter. It can also form
macromolecular complex by cooperating with other proteins and performs many important
cellular process. Recently it seems to interfere with the pathways of inflammation and
apoptosis. Hence a defective CFTR affects many functions that include airways, pancreatic
function, bile ducts, intestines and can cause many pathological conditions like inflammation
and cancers. A cohort study conducted by neglia et al based on association of CF and Cancer,
where he observed the ratio of observed to expected malignancy frequency is 0.8. Many
interpretation by investigators about the basic mechanism between CF and Cancer has been
published. The surplus mechanism is that defect of CFTR in pancreas causes ion transport
defect that results in obstruction of pancreatic duct which is followed by inflammation which
may give rise to Cancer. Wild Type CFTR reduces tumour progression by inhibiting MUC 4
protein a proto oncogene. Many studies conclusively says that tumour microenvironment and
other tumour causing signalling pathways may be altered due to CFTR downregulation in
Cystic Fibrosis. This downregulation of CFTR may also cause drug resistance in colon cancer
cells. As its main function to interact with other proteins such as ZO 1, E Cadherin, MRP
2( Multidrug Resistance Protein 2. These interaction may inhibit tumour growth which is
absent in CF patients. Also functional CFTR downregulate NFkB signalling pathways that
shows role in Inflammation and cancer metastasis. CFTR expression differs from organ to
organ where it functions may also differ. For example CFTR expression in pancreas causes
excretion whereas in macrophages the functional CFTR has role in Cytokine production. In
this review the basic focus is on Cystic Fibrosis which has defective CFTR and its role in
cancer with more prominent towards Breast Cancer. Also the role between therapeutics of
CFTR and Breast Cancer is proceeded. This review ends with future prospects of gained
mechanism aspect between CF and cancer and conclusion.

CYSTIC FIBROSIS AND BREAST CANCER

CFTR role in breast cancer is investigated and the results are controversial. Breast
Cancer rate is less in CF patients. It was due to the mutated CFTR that didn’t excrete ATP in
the lumen of gut that resulted in high ATP in blood that may inhibit Breast cancer growth.
The Antineoplastic activity of ATP were first shown in early 80s where colon and pancreatic
cancer cells are inhibited due to administration of exogenous ATP. In many paper it is said
that ATP when binds to purinergic receptor shows anti-tumour effect but it is also said to have
many pro- tumorigenic activities such as promoting metastasis. Later it is concluded that ATP
has biphasic action and it act as a double edge sword.

ROLE OF ATP IN INHIBITING CANCER GROWTH AND METASTASIS

The ATP released from the cells acts as a agonist for P2X receptor which is expressed
at high rate in invasive ductal and lobular breast cancer cells and inhibits cancer growth and
metastasis but at higher rate it promoted metastasis.

When ATP binds to P2X a purinergic receptor, it prevented cancer growth and
metastasis but at the same time the ecto ATPases expressed in the cancer cells hydrolyse
those unstable ATP into ADP, AMP and Adenosine. The CD 39 hydrolyse ATP to ADP and
AMP whereas CD 73 hydrolyse AMP to adenosine. This Adenosine act as a tumour
progressing agent by binding to A2A receptor that is also present in cancer cells and promotes
metastasis rate. This effect was not observed in non hydrolysable ATP lambda that is an
analogue of ATP because it cannot be converted to Adenosine and so it inhibited breast
cancer in a dose dependent manner. Also ecto ATPases inhibitor can also prevent hydrolysis
of ATP and it can efficiently prevent breast cancer growth by inhibiting formation of
adenosine. Here ATP and adenosis has opposing effects where ATP by binding to its receptor
inhibits cancer growth and metastasis whereas Adenosine promotes cancer growth and
metastasis by binding to A2A receptor. The adenosine function can be inhibited by using
Adenosine receptor antagonist. This mechanism provide us both the inhibition and promoting
role of ATP. Adenosine residues is found high in breast cancer cells because when adenosine
binds to its receptor it causes metastasis that forms hypoxic microenvironment which
increases the level of ecto ATPases in cancer cells that converts more ATP, leading to more
metastasis and this cycle continues leading to more and more de severe condition.

ATP and adenosine binds to a Purinergic receptor P1 and P2. The main ligand of P1 is
Adenosine and the main ligand of P2 is ATP and ADP. The study of these receptors in
various cancer cell line will help us to fine new therapeutic strategy.

METASTASIS DUE TO MUTATED CFTR

The EMT process is the main event that occurs during metastasis. This is promoted by
mutated CFTR, hence CF patient have more metastasis rate of breast cancer . The mechanism
is as follows.

In functional CFTR, the CFTR gene inhibits TRADD an adaptor protein that results in
inhibition of NFkB signalling pathway leads to deactivation of metastasis and inflammation
whereas, In mutated CFTR, the CFTR gene do not inhibits TRADD that leads to activation of
NFkB signalling pathways resulting in metastasis and inflammation.
CFTR AND OTHER CANCERS

Due to the mutated CFTR there is 1.5 fold increase in lung cancer which is caused
due to the aberrant epigenetic modification like DNA methylation in a cytosine preceeding
guanine CpG which can results in tumour suppressor genes silencing promoting lung cancer
rate. This was proved when a human adenocarcinoma of lungs was treated with
demethylation agent and the function of CFTR was regained. In another study, low CFTR
expression results in advanced cancer metastasis stage. Similar findings were also seen in
colon cancer. This may show that the functional CFTR has a inhibitory role of cancer growth
and progression of lung cancer. CFTR also has roles in inhibiting NFkB signalling pathway
that causes inflammation and cancer. Prostate Cancer also shows hypermethylation of CFTR
promoter with high gleason score and Ki67 index.