Question

As the cancer expert in the Biology Department at your school, NBC news contacts you to discuss the effects of bisphenol A (BPA) exposure on cancer risk. The reporter is very interested as she has read several articles on this topic. In particular she wants you to explain the following:

The reporter has read that in utero exposure increases the risk of mammary cancers in offspring. She wants you to explain the mechanism by which BPA may be increasing the risk of mammary cancers in the offspring.

Answer 1

BPA is a weak estrogen, which affects the gene expression in breast throughout life, It is an endocrine disrupting chemical found in environment . Particularly in plastics used in everyday life which interferes in the functioning of hormones.This interference leads to adverse developmental , reproductive, neurological and immune effects on human.

When a pregnant mice was treated with BPA it is found that the mammary glands in these treated mice offsprings produced a high level almost two times EZH2 , a protein which controls the expression of all the genes.

Higher production of EZH2 is associated with increased risk of breast cancer in humans. These endocrine disruptors promote hormone dependent cancer development by modulating the epigenetic mechanism .( Epigenetics is the study of heritable changes in gene expression taking place , without changing the DNA sequence. Epigenetic mechanisms includes DNA methylation, histone modification acetylation, methylation, phosphorylation, ubiquitination, sumoylation and ADP ribosylation), and expression of non-coding RNAs (including microRNAs).

The in-utero exposure of low doses of bisphenol A (BPA), may cause DNA hypermethylation/hypomethylation at CpG islands near the gene promoter regions, histone modifications (acetylation, methylation, phosphorylation, ubiquitination, sumoylation and ADP ribosylation), and expression of non-coding RNAs, including microRNAs. These epigenetic changes can induce upward or downward alterations of gene expression. Which may remain throughout life. These permanent changes will cause adverse health effects like neural and immune disorders, infertility, and late-onset complex diseases ( like breast cancers and diabetes).

BPA can cross the placenta at the time of fetal development, altering the fetal target organs and puts impact on the abundance and genomic distribution of epigenetic modification and simultaneously changes the gene expresssion which remains throughout life, increasing the risk of mammary cancer in the offspring.

A study in an ovarectomized rat showed that , when it is exposed to BPA it showed the level of EZH2 increased by two times , because BPA induced the hiring of MCC2/3 methylase and p300/CBP along with ER to increase EZH2 in breast cancer cells.

BPA exposure also led to increased expresssion of mammary gland development gene HOXC6 , this led to increase in H3K4 trimethylation and acetylation at HOXC6 promoter.Induced expresssion of HOXC6 and HOXC6 dependent tumor growth factor , this favouredthe colony formation of breast cancer cells.

BPA also promoted HOTAIR ,which is responsible for breast cancer progress.

Exposure to BPA also induced ESR1 promoter hypermethylation in breast cancer cells .

all these led to the alteration of the estrogen signalling leading to develoment of breast cancer.