Association of estrogen receptor-α and progesterone receptor A expression with hormonal mammary carcinogenesis: role of the host microenvironmentReportar como inadecuado

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Breast Cancer Research

, 9:R22

First Online: 06 March 2007Received: 12 August 2006Revised: 14 February 2007Accepted: 06 March 2007


IntroductionMedroxyprogesterone acetate MPA induces estrogen receptor ER-positive and progesterone receptor PR-positive ductal invasive mammary carcinomas in BALB-c mice. We sought to reproduce this MPA cancer model in C57BL-6 mice because of their widespread use in genetic engineering. Within this experimental setting, we studied the carcinogenic effects of MPA, the morphologic changes in mammary glands that are induced by MPA and progesterone, and the levels of ER and PR expression in MPA-treated and progesterone-treated mammary glands. Finally, we evaluated whether the differences found between BALB-c and C57BL-6 mouse strains were due to intrinsic differences in epithelial cells.

MethodsThe carcinogenic effect of MPA was evaluated in C57BL-6 mice using protocols proven to be carcinogenic in BALB-c mice. In addition, BALB-c and C57BL-6 females were treated with progesterone or MPA for 1 or 2 months, and mammary glands were excised for histologic studies and for immunohistochemical and Western blot evaluation of ER and PR. Hormone levels were determined by radioimmunoassay. Isolated mammary epithelial cells were transplanted into cleared fat pads of 21-day-old female Swiss nu-nu mice or control congenic animals.

ResultsMPA failed to induce mammary carcinomas or significant morphologic changes in the mammary glands of C57BL-6 mice. The expression of ER-α and PR isoform A in virgin mice was surprisingly much higher in BALB-c than in C57BL-6 mammary glands, and both receptors were downregulated in progestin-treated BALB-c mice P < 0.05. PR isoform B levels were low in virgin control mice and increased after progestin treatment in both strains. ER-β expression followed a similar trend. No differences in hormone levels were found between strains. Surprisingly, the transplantation of the epithelial mammary gland cells of both strains into the cleared fat pads of Swiss nu-nu mice abolished the mammary gland morphologic differences and the ER and PR differences between strains.

ConclusionC57BL-6 mammary glands are resistant to MPA-induced carcinogenesis and to hormone action. MPA and progesterone have different effects on mammary glands. Low ER-α and PR-A levels in untreated mammary glands may be associated with a low-risk breast cancer profile. Although we cannot at this time rule out the participation of other, untested factors, our findings implicate the stroma as playing a crucial role in the strain-specific differential hormone receptor expression and hormone responsiveness.

AbbreviationsANOVAanalysis of variance


EGFepidermal grwoth factor

ERestrogen receptor

IGFinsulin-like growth factor

MPAmedroxyprogesterone acetate

MMTVmurine mammary tumor virus

NIDDKNational Institute of Diabetes and Digestive and Kidney Diseases

PBSTphosphate-buffered saline-Tween

PCRpolymerase chain reaction

PRprogesterone receptor

Electronic supplementary materialThe online version of this article doi:10.1186-bcr1660 contains supplementary material, which is available to authorized users.

Guadalupe Montero Girard, Silvia I Vanzulli contributed equally to this work.

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Autor: Guadalupe Montero Girard - Silvia I Vanzulli - Juan Pablo Cerliani - María Cecilia Bottino - Julieta Bolado - Jorge Vela


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