The Relationship of Circulating Prolactin Levels to the Size Of

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77http://www.TurkJBiochem.com SSN 1303-829X (electronic) 0250-4685 (printed)

Trk Biyokimya Dergisi [Turkish Journal of Biochemistry - Turk J Biochem] 2004; 29 (4); 277-281.

The Relationship of Circulating Prolactin Levels to TheSize of Primary Tumor in Breast Cancer Patients

Yayn tar h Aralk, 2004 TurkJB ochem.comAratrma Makalesi [Research Article]

Z ata Mu ag c 1)

Hamza Mu ag c 2)

ZET

eme anser n e pro a t n n (PRL) ro onusun a ver er e r. Bu hormoneme anser n n a amas ve ge mes n e, nsan a smen, em rgen hayvan ar a se

nemli bir role sahip olabilmektedir.

u a mann amac PRLn n o am a sev ye er e meme anser hasta arnnpr mer tmr parametre er arasn a o as y aratrma t r. Deneyse gru u memekanseri tehisleri histolojik olarak onaylanm 46 kadn hasta oluturmaktadr. ki kon-

trol grubu ile allmtr: klinik olarak salkl bulunan kadnlar (40) ve dier kansertiplerinden birine sahip kadn hastalar (33). Primer tmr parametreleri (histolojik tan,ar amann ereces , yer e m ve y ) saptanm ve sonu ar nonparametr

test er u an ara eer en r m t r.

e av ye a anma an nce en PRLn n o am zey er , ontro grup ary akarlatrldnda meme kanserli hastalarda nemli derecede yksek bulunmutur.

edavi ncesi hiperprolaktinemili meme kanseri hastalarnn primer tmrlerinin ortala-a oyutu (U=125.5, p< 0.01), normopro a t nem ye sah p o an ar an nem erece e

aha y tr. H perpro a t nem meme anser hasta arn a pr mer tmr y e PRL arasn a hesap anan ore asyon sa t stat st se o ara nem r (r = 0. 8,

p< 0.0001). Normopro a t nem ye sah p o an meme anser hasta ar ve er tmortiplerine sahip olan hastalarda bu korelasyon tespit edilmemitir.

zellikle hiperprolaktinemili meme kanseri hastalarnda primer tmr byklnnRLn n serum zey er ne oru an a o a , ama u urumun ar amaya

a r u rum o ma sy ene r.na tar e me er: pro a t n, meme anser , pr mer tmr

(1) epartment o B ochem stry, and (2) Cha r n

Oncology, Med cal aculty Un vers ty o Tuzla,

Bosn a-Hezregov na

azma res[Correspondence Address]

Zlata Mu ag c, Med cal aculty Un vers ty o Tuzla,n verz tetska 1, 75000 Tuzla, ax:++ 387 35 300 01,

e-ma l: g [email protected]

ayt tar h 1.4.2004; kabul tar h 20.12.2004[Rece ved 1.4.2004; accepted 20.12.2004]

[Meme Kanserli Hastalarda Primer Tmr Boyutu ile Dolamdaki ProlaktinDzeylerinin likisi]

[Published online December, 2004]

at ona e: ata a out the ro e o pro act n (PRL) n reast cancer pat ents are contro-ers a . Th s hormone m ght potent a y p ay an mportant ro e n reast cancer n t a-

t on an eve opment n ro ents, as we as, at east part y, n humans. The a m o th stu y was to nvest gate the poss e re at onsh p etween c rcu at ng eve s o PRL an

parameters of primary tumor in breast cancer patients.he ma n exper menta group cons ste o 4 ema e pat ents w th h sto og ca yon rme agnos s o reast cancer. There were two contro groups: apparent y c n -a y hea thy women (40), an ema e pat ents w th other types an ocat ons o cancer33). Baseline levels of PRL were determined both in the main and in control groups.arameters of primary tumor (histological diagnosis, degree of differentiation, location,nd size) have been determined. Results were processed by means of nonparametric

tests.

he c rcu at ng eve s o PRL e ore treatment were s gn cant y h gher n reastancer patients in comparison to controls. The average size of the primary tumor in

breast cancer patients with hyperprolactinemia before treatment was significantly higherU=125.5, p


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278Turk J Biochem, 2004; 29(4); 277-281. ujagic and Mujagic

INTRODUCTIONormal breast tissue cells are sensitive to a umber of

hormones among which estrogens and prolactin (PRL)have the most dramatical effect. Malignant breast tissuecells can behave in this respect similar to normal cells.

This mostly depends on the degree of their differentia-tion and growth. More differentiated cells usually pos-sess hormone receptors on their membranes very muchalike normal cells, and according to that, can respond tonormal hormonal stimulation. Less differentiated cellsescape normal hormonal regulation from loss of hormo-ne receptors.

Data about the function of PRL in mammary neoplasiaare controversial. PRL was first recognised as a hormonethat might significantly contribute to both the pathoge-nesis and progression of rodent mammary neoplasia (1).It is a major tumor mitogen in rodents, and excess PRL

has been shown to induce breast cancer in mice (2, 3).The role of PRL in human breast cancer has been poorlyunderstood until recently. The contribution of PRL tothe pathogenesis and progression of human breast cancerat the cellular, transgenic, and epidemiological levels isincreasingly appreciated. There is firm evidence docu-menting a direct stimulatory effect of PRL on mammaryepithelial cells (4), and breast cancer cells (5, 6, 7) invitro. Acting at the endocrine and autocrine/paracrineevels, PRL functions to stimulate the growth and moti-ity of the human breast cancer cells (8). The majority of

breast cancers express prolactin receptor (PRLR), mea-ning PRL was active in the tumors (8, 9, 10). The PRL/PRLR complex associates with, and activates severalsignaling networks that are shared with other membersof the ytokine receptor superfamily (10). It was recentlyidentified intranuclear function of PRL in the initiationof the human breast cancer (11, 12). There also are someepidemiological data suggest a relatively strong positiveassotiation between circulating levels of PRL and breastcancer risk in women (13, 14).

With the goal of evaluation of clinical usefullness ofPRL as a potential marker in breast cancer patients we

examined correlations of its circulating levels with someparameters of primary tumor (size, and degree of diffe-rentiation).

PATIENTS AND METHODSPatients

It was prospective randomised study with defined cryte-ria for patients inclusion.

The inclusion cryteria

A. Breast cancer patients:

- Non or occasional smokers,

Non alcoholic drinkers,

Occasional or no coffee drinkers,

No other drug users,

No other major illnesses,

Histologically proven breast cancer,

Currently under no treatment,

Age interval 38-65 years,

General clinical status fair.

B. Other cancer patients:

Besides the major cancer illness, other cryteria wereexactly the same as in main experimental group.

. Healthy control group:

The inclusion cryteria for the healthy control group,besides the absence of malignant or any other majordebilitating disease, were the same as in other two gro-

ups.The main experimental group consisted of 46 femalehistologically confirmed breast cancer patients with ange interval 38-65 years. The circulating levels of PRL

were measured in all of them before any therapy (base-ine levels), and then at regular time intervals during

the observation period. Parameters of primary tumorhistological diagnosis, degree of differentiation, locati-

on, and size) have been determined in all of them. Thisroup was further divided into two subgroups according

to their serum PRL before therapy: hyperprolactinemicones (23 patients), with average circulating PRL of morethan 520 mU/L; and normoprolactinemic (23 patients),having PRL between 52 and 520 mU/L.

There were two control groups designated as I, and II.Group I consisted of 40 clinically healthy women withn age interval 38-65 years. All of them had normal

mammograms. The circulating levels of PRL weremeasured in all of them at least three times during theobservation period.

Group II consisted of 33 female patients having cancerof different histological origin and location with an ageinterval 38-65 years. Majority of them have colon and

ung cancer. The same data as in the main group havebeen collected in all of them. Circulating levels of PRLbefore any therapy were measured in all of them, andater again at regular time intervals during the observa-

tion period.

Estimation of primary tumor parameters

istological diagnosis was performed on fresh speci-mens obtained by means of needle biopsy, or on spe-cimens taken at surgery. Degree of differentiation wasestimated according to well established criteria (15).

ize of primary tumor was determined first by palpation,nd then measured with a caliper always in two rightngle perpendicular diameters. The estimated size was


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79Turk J Biochem, 2004; 29(4); 277-281. ujagi and Mujagi

in most cases replaced by data given in written patholo-gical reports from actual surgical operations.

Determination of blood levels of PRL

Blood samples were drawn under sterile conditions

at eight hours in the morning each time, centrifugedat 3000 rpm for 10 minutes under room temperature,and serum was stored at 20oC until processed. Thecirculating levels of PRL were determined by means ofradioimmunoassay (RIA) method using commerciallyavaliable kits (Serono). Range of normal values was52-520 mU/L.

Statistical analysis of results

The nature of distribution of quantitive variables waschecked using distribution histograms with P-P (proba-bility plots), and detrended probability plots. The resultswere evaluated using nonparametric Mann-Whitney test,and Spearmans correlation coefficient using two sidedsignificance of p values, with calculated mean valuesand standard errors. The p values less than 0.05 wereconsidered as statistical significant. All results wereprocessed in SPSS version 10.

RESULTS

The circulating levels of PRL

Baseline levels of PRL were significantly higher (

=765, p


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hyperprolactinemic breast cancer patients in comparisonto those with normoprolactinemia (table II). There wasa significant positive correlation between the baselineevels of PRL and the size of primary tumor in all breast

cancer patients and, especially, in hyperprolactinemicones, while in normoprolactinemic patients and inpatients with various other cancers such a connec-tion did not exist (table III). There was no correlationbetween the PRL levels and the degree of differentiationof primary tumor either in the group of all breast cancerpatients or in hyperprolactinemic ones. The correlationwas found only in the group of normoprolactinemicpatients (table IV). These findings support the hypoth-esis that breast cancer cells can synthesize and secretePRL. The circulating levels of PRL are thus directlydependable on the size of primary tumor, but this is notdifferentiation dependent phenomenon which means thateither cells (dedifferentiated and mature) can synthesizeand secrete this hormone. This finding is in accordancewith other results published before (7, 9, 10, 16, 17). Theresults in this paper also suggest potential stimulative

effect of PRL on the growth of breast cancer cells but themechanism of action as well as the origin of circulatingPRL and its effect on breast cancer cells are still unclear.

It is now recognize that both endocrine and autocrine/paracrine sources of PRL exist in mammals (17). It haslready been documented that PRL plays an important

role in the initiation and differentiation of breast cancercells in rodents (2, 3, 10, 17), and in humans in vitro (10,

7), but its role as an etiologic factor in the initiationof breast cancer in humans has not been firmly docu-mented. However, the results of other studies support theconclusion that PRL can be synthesized and secreted bybreast cancer cells and that it can act as a local growthpromotor in the surrounding of these cells (7, 18, 19).It remains to be clarified whether for the stimulation ofrowth of breast cancer cells is responsible autocrine

PRL, or endocrine PRL secreted by pituitary or othertissues, or possible stress, or all of them. The molecu-ar structure of the PRLR seems to remain intact in

tumor tissue, and systemic and local production of PRL

may participate in tumor cell growth and proliferationthrough functional receptors (20). Results in our studydocument a positive correlation between the size of pri-mary tumor and the circulating levels of PRL, favoringthe opinion that for the development and potentiation ofthe growth of breast cancer cells more responsibility lieson the side of endocrine (hypophyseal) PRL. However,the origin of circulating PRL in breast cancer patients isnot clear. It is not known yet whether it originates exclu-sively from the pituitary or it also might be a product ofbreast cancer cells. Furthermore, it still remains to beclarified whether hyperprolactinemia is the result or the

cause of breast cancer. The fact that antihyperprolactine-mic drugs are very effective in lowering the circulatingevels of PRL but, in majority of cases, ineffective in

controlling the development of breast cancer (17) backsup the hypothesis that both endocrine and autocrine PRLre involved in breast carcinogenesis. Probably, the best

situated explanation is that endocrine PRL is responsiblefor initiation, and autocrine for perpetuation of carcino-enic process.

esults of our study document positive correlationbetween the size of primary tumor and the circulatingevels of PRL favoring the conclusion that serum levels

of PRL are, probably, directly dependable on the sizeof primary tumor in breast cancer patients, especially inthose with hyperprolactinemia, but this is not differentia-tion dependent phenomenon.

280Turk J Biochem, 2004; 29(4); 277-281. ujagic and Mujagic

Table III. The correlation between the circulating levels of prolactin

PRL) before treatment and the size of primary tumor in breast cancer

patients and in patients with other types and locations of cancer.

Group/numbePRL (mU/L)

meanS.E.

Size of

primary tumo

(cm2)

r* p

All breast

ancer pat ents10.5 5.3 8.81.3 0.37 0.01

yperprolact nem a 929.087.0 1.42.4 0. 8 0.0001

ormoprolact nem a 292.01 .5 .10.7 -0.15 .5

Other cancer

pat ents524.1+- 5.2 8.33.8 0.09 0. 3

* Spearmans correlaton coefficient

Table IV. The correlation between the circulating levels of prolactinPRL) before treatment and the degree of differentiation of primary

tumor in breast cancer patients and in patients with other types and

locations of cancer.

Group/numbePRL (mU/L)

meanS.E.

Degree of

d erent at on**r* p

All breast

ancer pat ents89.8+- 2.5 .780.11 0.01 .93

yperprolact nem a 27.4+-108.4 .730.15 -0.33 .12

ormoprolactinemia 488.9+-25.5 .880.17 0.51 .01

Other cancer

pat ents524.1+-65.2 .700.16 -0.07 .73

* Spearmans correlaton coefficient

** 1=well differentiated, 2=medium differentiated, 3=poorly differ-

entiated


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81Turk J Biochem, 2004; 29(4); 277-281. ujagi and Mujagi

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References

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The Relationship of Circulating Prolactin Levels to the Size Of