Local over-expression of prolactin in differentiating mouse mammary gland induces functional defects and benign lesions, but no carcinoma

Abstract

Experimental, clinical, and epidemiological data support the growth-promoting role of endocrine prolactin (PRL) in mammary tumors. PRL is also produced by the breast, where it is now recognized to act as a growth/survival factor via autocrine/paracrine mechanisms. Recent transgenic (Tg) mouse models have revealed the pro-oncogenic effect of PRL over-expression in virgin mammary glands. To address the question whether PRL tumorigenicity was maintained on differentiated mammary glands, we generated mammaryspecific Tg mice expressing human (h)PRL under the control of the milk whey acidic protein promoter, which directs autocrine hPRL over-expression in late gestation throughout lactation. Minimal levels of transgene expression were detected in the mammary glands of virgin animals, which at best induced partial ductal branching and lobulo-alveolar structures in older nulliparous females. As expected, expression of mammary hPRL dramatically increased at the end of first pregnancy, and from this point it never returned to baseline, although it peaked at each gestation/lactation cycle. Over-expression of hPRL that starts when the gland is already well into the differentiation process led to various morphological mammary alterations, including abnormally differentiated epithelium, atropy of the myoepithelial layer, dilated ducts, cysts, and lymphocytic infiltrates. These phenotypes tended to worsen with successive pregnancies, also reflecting cumulative damage of failure of involution. Although some older, multiparous females developed benign tumors (papillomas and metaplasias), none of the animals studied developed mammary carcinomas. In addition, we noticed that half of the Tg females exhibited lactation defects, leading to significantly increased pup mortality. This phenotype was due neither to failure of milk production nor to modification of its protein content, but rather it was correlated to lipid enrichment of the milk, which, in combination with profoundly altered morphology of the gland, led to impaired milk extrusion through the nipple. In summary, these data show that over-expression of autocrine hPRL in a differentiating mammary gland induces dramatic functional and morphological defects, but not carcinoma. This deserves further investigations on the emerging concept that autocrine PRL may have different effects on pathological development of the mammary gland depending on the differentiation state of the latter.

Tyrosine Phosphorylation of Grb2: Role in Prolactin/Epidermal Growth Factor Cross Talk in Mammary Epithelial Cell Growth and Differentiation

“…While PRL has been described to play a proliferative and tumorigenic role in the mammary epithelium (4,29,32), the overexpression of PRL in the differentiated mammary epithelium resulted in altered alveologenesis, yet no carcinomas were detected (24), suggesting that the state of differentiation of mammary epithelial cells may be an important determinant in specifying the role of PRL as a proliferative agent. While these data indicate that the role of PRL in mammary cell proliferation is complex and requires further investigation, our data indicate that in differentiated mammary epithelial cells, PRL is nonproliferative, and moreover, PRL can attenuate growth factor-induced cell proliferation.…”

Identification of a gain-of-function mutation of the prolactin receptor in women with benign breast tumors

“…Unfortunately, this study failed to reveal whether these morphological anomalies developed into mammary tumors because only young animals were used (24). We recently showed that transgenic mice over-expressing Prl in the differentiating/lactating mammary gland developed various benign lesions from the age of approximately 1 year (25). Using a permanently active promoter, others showed that autocrine Prl induced mammary carcinomas in virgin females from the age of approximately 15 months (26).…”

“…Using a permanently active promoter, others showed that autocrine Prl induced mammary carcinomas in virgin females from the age of approximately 15 months (26). Although the mechanisms leading to the development of benign versus malignant tumors are not yet fully understood, they may involve various parameters such as genetic background or the state of differentiation of the gland (25), these studies highlighted the ability of PrlR-triggered pathways to promote mammary tumorogenesis in rodents. In humans, the link between Prl levels and breast carcinogenesis has recently emerged from the Nurse Health study (27,28).…”

Autocrine prolactin: an emerging market for homegrown (prolactin) despite the imports

“…Despite their histological differences, the NRL-prolactin-induced tumors tend to belong to the estrogen-resistant luminal subtype of breast cancer (Arendt et al 2011). Interestingly, overexpression of prolactin under the control of whey acidic protein promoter (WAP) does not induce mammary carcinogenesis, suggesting that the differentiation state of cells in which prolactin is overexpressed may influence the ability of prolactin to induce tumorigenesis (Manhes 2006). In addition to initiating transformation by itself, prolactin also cooperates with other prominent regulators of mammary tumorigenesis.…”