Breast cancer and aspirin

[Guest guest]

Hi All,

The below pdf-available paper below and the paper to which it refers

are on breast cancer prevention by aspirin. CRers have little heart

disease risk and so may not warrant using aspirin. Cancer and breast

cancer risk are minimized also. But we do expect that all of us will

die sometime. Do we take aspirin or not? I have opted for reducing

the risk of bleeding, stroke and other hemorrhaging.

JAMA, May 26, 2004; 291 (20) 2488-2489

Aspirin and Breast Cancer Prevention

The Estrogen Connection

N. DuBois

See also p 2433.

IN THIS ISSUE OF THE JOURNAL,TERRY ET AL 1 REPORT THAT

aspirin use in women is associated with a significant re-duction

in the risk of breast cancer, especially for hor-mone

receptor–positive tumors. Previous studies have

examined the relationship between breast cancer risk and

aspirin or other nonsteroidal anti-inflammatory drug

(NSAID) use but have not delineated different subtypes of

breast cancers to determine this kind of correlation. This

report is the first to examine whether the protective effect

of aspirin varies with estrogen receptor (ER) or progester-one

receptor (PR) status. With the genomic and proteomic

revolution well underway, it is becoming quite clear that

there are distinct differences in molecular signatures be-tween

tumors derived from the same organ. It is well known

that the hormonal responsiveness of breast cancers is im-portant

for determining the treatment regimen and can affect

the clinical outcome. Thus, it is not surprising that one sub-set

of breast cancers may be more responsive to a particu-lar

prevention strategy than another.

More than 80 million aspirin tablets are consumed each

day in the United States.2 This 100-year-old drug is one of

the most commercially successful pharmaceutical agents ever

produced. Yet despite the widespread use of aspirin over sev-eral

decades, one of the mechanisms of its action was not

really known until the early 1970s when Vane 3 found that

it blocked the production of " proinflammatory " prostaglan-dins.

Based on this discovery, Vane and 2 Swedish scien-tists,

Bergstrom and sson, won the Nobel Prize in

Physiology or Medicine in 1982. 4 Later it was found that

aspirin binds covalently and blocks the active site of the pros-

taglandin-

endoperoxide synthase 1 enzyme (often referred

to as cyclooxygenase 1 [COX-1]).5 A second, inducible form

of prostaglandin-endoperoxide synthase (COX-2), which is

also affected by aspirin, was subsequently cloned and the

complementary DNA sequence was reported in 1991 by at

least 3 groups.6-8

Aspirin use has been associated with a reduction in mor-tality

from cardiovascular disease 9 and colorectal cancer.10

Observational studies reporting a protective effect of aspi-rin

on breast cancer have been mixed. Liu et al 11 addressed

the question experimentally by creating COX-2 transgenic

mice in which expression was driven by the murine mam-mary

tumor virus (MMTV) promoter. Breast carcinomas

developed spontaneously in multiparous female MMTV–

COX-2 mice, indicating that COX-2 alone has oncogenic

potential in the mammary gland. Chang et al 12 later delin-eated

the molecular mechanism(s) by which COX-2–

derived prostaglandin E2 (PGE2) induces tumor-associated

angiogenesis, which is required for the initiation and/or

progression of mammary cancer in MMTV–COX-2 mice.

These investigators reported that PGE2 induced angiogen-esis

at the earliest stage of tumor development, even before

PGE2-induced mammary gland hyperplasia. They also

found that the nonselective NSAID indomethacin inhibited

both PGE2-induced angiogenesis and breast tumor pro-gression

and confirmed the role of COX-2 by using the

COX-2 selective inhibitor celecoxib. This work clearly

demonstrated that COX-2 overexpression can cause breast

cancer in mice.

The current report by Terry et al finds that the inverse

association between aspirin use and breast cancer was clearly

evident for every patient subgroup except for those with nega-tive

hormone receptor status (ER & #8722;PR & #8722;). The association was

strongest among frequent aspirin users. However, acetami-nophen

use was not associated with protection in any sub-group.

These findings are noteworthy and may reveal some

important mechanistic insight about a connection between

aspirin and estrogen. In 1996, a report by Subbaramaiah et

al 13 suggested transcriptional activation of COX-2 in trans-formed

mammary epithelial cells. That same year, Zhao et

al 14 demonstrated that PGE2 can induce aromatase expres-sion

leading to increased estrogen production in mam-mary

adipose stromal cells. In 1999, Soslow et al 15 found

that COX-2 was expressed in breast ductal carcinoma in situ

and in breast cancers. Recently, other investigators re-ported

that COX-2 is up-regulated in the normal adjacent

epithelium to ductal carcinoma in situ and that COX-2 over-expression

coincides with focal areas of p16INK4a hyper-methylation

in vivo that could represent early neoplastic

changes leading to breast cancer.16,17

Taken collectively, these studies provide a clear ratio-nale

for a role of COX and prostaglandins in breast cancer.

Blocking COX activity with aspirin or other NSAIDs would

inhibit aromatase induction and result in lower estrogen lev-els

(FIGURE). Therefore, the observation that receptor-positive

tumors are more responsive to aspirin is consis-tent

with these preclinical and clinical observations. This

association needs to be confirmed before clinicians can make

any definite recommendations to patients at risk for breast

cancer. However, it does appear that there is emerging evi-dence

supporting a protective effect of aspirin in ER+ and

PR+ breast cancers.

Despite the longstanding and ubiquitous nature of aspi-rin

use, researchers are still exploring the clinical outcome

of aspirin treatment in humans. Unfortunately, all the answers

are not available and current information is insufficient to

make any definite recommendations to patients. Womenwho

take daily aspirin for cardiovascular indications may gain

additional benefits with regard to reduction in their risk for

certain cancers, such as hormone receptor & #8722;positive breast

cancer. However, the optimal aspirin dose or regimen required

to achieve a maximal reduction in cancer risk remains

unknown.

REFERENCES

1. Terry MB, Gammon MD, Zhang FF, et al. Association of frequency and

dura-tion

of aspirin use and hormone receptor status with breast cancer risk.

JAMA.

2004;291:2433-2440.

2. Vane JR. The fight against rheumatism: from willow bark to COX-1

sparing

drugs. J Physiol Pharmacol. 2000;51(4 pt 1):573-586.

3. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of

action for aspirin-like

drugs. Nature. 1971;231:232-235.

4. Raju TN. The Nobel chronicles, 1982: Sune Karl Bergstrom (b 1916);

Bengt In-gemar

sson (b 1934); Vane (b 1927). Lancet. 1999;354:

1914.

5. Van Der Ouderaa FJ, Buytenhek M, Nugteren DH, Van Dorp DA.

Acetylation

of prostaglandin endoperoxide synthetase with acetylsalicylic acid.

Eur J Bio-chem.

1980;109:1-8.

6. Kujubu DA, Fletcher BS, Varnum BC, Lim RW, Herschman HR. TIS10, a

phor-bol

ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a

novel

prostaglandin synthase/cyclooxygenase homologue. J Biol Chem.

1991;266:

12866-12872.

7. Xie W, Chipman J, on D, son R, D. Expression of

a mitogen-responsive

gene encoding prostaglandin synthase is regulated by mRNA splicing.

Proc Natl Acad Sci U S A. 1991;88:2692-2696.

8. O'Banion MK, Sadowski HB, Winn V, Young DA. A serum- and

glucocorticoid-regulated

4-kilobase mRNA encodes a cyclooxygenase-related protein. J Biol Chem.

1991;266:23261-23267.

9. Mueller RL, Scheidt S. History of drugs for thrombotic disease:

discovery, de-velopment,

and directions for the future. Circulation. 1994;89:432-449.

10. Smalley W, DuBois RN. Colorectal cancer and non steroidal anti-

inflammatory

drugs. Adv Pharmacol. 1997;39:1-20.

11. Liu HL, Chang SH, Narko K, et al. Over-expression of

cyclooxygenase-2 is

sufficient to induce tumorigenesis in transgenic mice. J Biol Chem.

2001;276:

18563-18569.

12. Chang SH, Liu CH, Conway R, et al. Role of prostaglandin E2-

dependent an-giogenic

switch in cyclooxygenase 2-induced breast cancer progression. Proc

Natl

Acad Sci U S A. 2004;101:591-596.

13. Subbaramaiah K, Telang N, Ramonetti JT, et al. Transcription of

cyclooxy-genase-

2 is enhanced in transformed mammary epithelial cells. Cancer Res.

1996;

56:4424-4429.

14. Zhao Y, Agarwal VR, Mendelson CR, Simpson ER. Estrogen

biosynthesis proxi-mal

to a breast tumor is stimulated by PGE2 via cyclic AMP, leading to

activation

of promoter II of the CYP19 (aromatase) gene. Endocrinology.

1996;137:5739-

5742.

15. Soslow RA, Dannenberg AJ, Rush D, et al. COX-2 is expressed in

human

pulmonary, colonic, and mammary tumors. Cancer. 2000;89:2637-2645.

16. Crawford YG, Gauthier ML, Joubel A, et al. Histologically normal

human mam-mary

epithelia with silenced p16(INK4a) overexpress COX-2, promoting a pre-

malignant

program. Cancer Cell. 2004;5:263-273.

17. Shim V, Gauthier ML, Sudilovsky D, et al. Cyclooxygenase-2

expression is re-lated

to nuclear grade in ductal carcinoma in situ and is increased in its

normal

adjacent epithelium. Cancer Res. 2003;63:2347-2350.

Figure. Prostaglandin E2 Produced by Tumor Cells Stimulates

Expression of Cytochrome P450 Aromatase (CYP19) in Breast

Adipose Stromal Cells

BREAST ADIPOSE

STROMAL CELL

RECEPTOR-POSITIVE

BREAST CANCER CELL

COX-2

Increased

COX-2 Gene

Expression

Oncogenes

Growth Factors

Tumor Promoters

Proinflammatory

Mediators

Arachidonic

Acid

PGE 2 Receptor

Estrogen

Receptors Estrogen-Mediated

Gene Expression

Increased

Estrogen

Production

C19

Steroids

Proliferation of

Tumor Cells

PGH 2

PGG 2

PGE 2 Increased

Phosphorylated CREB

Increased

cAMP Production

Increased P450 Aromatase

Gene Expression

P450 Aromatase

NSAIDs

Overexpression of cyclooxygenase 2 (COX-2) in breast cancer cells

leads to changes

in tumor biology related to increased prostaglandin (PG) E2 levels.

This can affect

apoptosis, cell invasion, immune function, and tumor-associated

angiogenesis. PGE2

is also known to induce expression of aromatase via increased cyclic

adenosine

monophosphate (cAMP) production in breast adipose stromal cells.

Thus, estro-gen

synthesis is enhanced, which leads to increased proliferation of

tumor cells.

This paracrine loop could explain why inhibition of COX activity

could have a ben-eficial

effect on hormone receptor–positive breast cancers. NSAIDs indicates

non-steroidal

anti-inflammatory drugs; CREB, cAMP response element binding protein.

EDITORIAL